Genetics of Breast and Gynecologic Cancers (PDQ®) 3/8 –Health Professional Version - National Cancer Institute

Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version - National Cancer Institute

Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version

Other High-Penetrance Syndromes Associated With Breast and/or Gynecologic Cancers

Lynch syndrome

Lynch syndrome is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer.[309] The condition is caused by germline variants in the mismatch repair (MMR) genes, which are involved in repair of DNA mismatch variants.[310] The MLH1 and MSH2 genes are the most common susceptibility genes for Lynch syndrome, accounting for 80% to 90% of observed pathogenic variants,[311,312] followed by MSH6 and PMS2.[313-318] (Refer to the Lynch Syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

After colorectal cancer, endometrial cancer is the second hallmark cancer of a family with Lynch syndrome. Even in the original Family G, described by Dr. Aldred Scott Warthin, numerous family members were noted to have extracolonic cancers including endometrial cancer. Although the first version of the Amsterdam criteria did not include endometrial cancer,[319] in 1999, the Amsterdam criteria were revised to include endometrial cancer as extracolonic tumors associated with Lynch syndrome to identify families at risk.[320] In addition, the Bethesda guidelines in 1997 (revised in 2004) did include endometrial and ovarian cancers as Lynch syndrome–related cancers to prompt tumor testing for Lynch syndrome.[321,322]

The lifetime risk of ovarian carcinoma in females with Lynch syndrome is estimated to be as high as 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected Lynch syndrome.[323-328] Characteristics of Lynch syndrome–associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages I and II at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in carriers of BRCA pathogenic variants.[329,330]

The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[331-334] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[334] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [335] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[335] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[336] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1 carriers but not in carriers of other MMR variants.[337] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[338]

A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[339-342] although this has not been consistently observed.[343] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[339] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2 pathogenic variants.[340] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 105).[341] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[342] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[97]

Refer to the Lynch Syndrome section of the Clinical Management of Other Hereditary Breast and/or Gynecologic Cancer Syndromes section of this summary for information about clinical management of Lynch syndrome.

Li-Fraumeni syndrome (LFS)

Breast cancer is also a component of the rare LFS, in which germline variants of the TP53 gene on chromosome 17p have been documented. Located on chromosome 17p, TP53 encodes a 53kd nuclear phosphoprotein that binds DNA sequences and functions as a negative regulator of cell growth and proliferation in the setting of DNA damage. It is also an active component of programmed cell death.[344] Inactivation of the TP53 gene or disruption of the protein product is thought to allow the persistence of damaged DNA and the possible development of malignant cells.[345,346] Widely used clinical diagnostic criteria for LFS were originally developed by Chompret et al. in 2001 (called the Chompret Criteria) [347] and revised in 2009 based on additional emerging data.[348]

LFS is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma.[345,349,350]

Germline variants in TP53 are thought to account for fewer than 1% of breast cancer cases.[351] TP53-associated breast cancer is often HER2/neu-positive, in addition to being ER-positive, PR-positive, or both.[352-354] Evidence also exists that patients treated for a TP53-related tumor with chemotherapy or radiation therapy may be at risk of a treatment-related second malignancy.

Historical criteria for defining LFS

The term Li-Fraumeni syndrome was used for the first time in 1982,[355] and the following criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988 [356]:

1. Sarcoma before age 45 years;
2. An FDR with cancer before age 45 years; AND
3. Another close relative (FDR or second-degree relative [SDR]) with either cancer before age 45 years or a sarcoma at any age.

Subsequently in 2001, Chompret et al. [347] systematically developed clinical criteria for recommending TP53 genetic testing, with the narrow LFS tumor spectrum defined as sarcoma, brain tumors, breast cancer, and adrenocortical carcinoma. The criteria were as follows:

1. A proband affected by a narrow-spectrum tumor before age 36 years AND at least one FDR or SDR affected by a narrow-spectrum tumor (other than breast cancer if the proband is affected by breast cancer) before age 46 years or multiple primary tumors; OR
2. A proband with multiple primary tumors, two of which belong to the narrow spectrum and the first of which occurred before age 36 years, irrespective of family history; OR
3. A proband with adrenocortical carcinoma irrespective of the age at onset and family history.

These criteria were revised in 2009 [348] based on additional emerging data [346,357] as follows:

1. A proband with a tumor belonging to the LFS tumor spectrum* before age 46 years AND at least one FDR or SDR with a LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
2. A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
3. A patient with adrenocortical carcinoma or choroid plexus, irrespective of family history.

*The 2009 Chompret criteria defined the LFS tumor spectrum as including the following cancers: soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer.

In 2015, Bougeard et al. [350] revised the criteria based on data from 415 carriers of pathogenic variants, to include the presence of childhood anaplastic rhabdomyosarcoma and breast cancer before age 31 years as an indication for testing, similar to what is recommended for choroid plexus carcinoma and adrenocortical carcinoma. The criteria were revised as follows:

1. A proband with a tumor belonging to the LFS tumor spectrum** before age 46 years AND at least one FDR or SDR with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
2. A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
3. A patient with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
4. Breast cancer before age 31 years.

**The 2015 Chompret criteria defined the LFS tumor spectrum as including the following cancers: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, and adrenocortical carcinoma.

Clinical characteristics of LFS

Germline TP53 pathogenic variants were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing.[346] All families with a TP53 pathogenic variant had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 pathogenic variant, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 variants were found.

Subsequently, a large clinical series of patients from France who were tested primarily based on the 2009 version of the Chompret criteria [348] included 415 carriers of pathogenic variants from 214 families.[350] In this study, 43% of carriers had multiple malignancies, and the mean age at first tumor onset was 24.9 years. The childhood tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas, CNS tumors, and soft tissue sarcomas (present in 23%–30% collectively), whereas the adult tumor spectrum primarily encompassed breast cancer (79% of females) and soft tissue sarcomas (27% of carriers). The TP53 pathogenic variant detection rate was 6% among females younger than 31 years with breast cancer and no additional features suggestive of LFS. Evaluation of genotype-phenotype correlations indicated a gradient of clinical severity, with a significantly lower mean age at onset among those with dominant-negative missense variants (21.3 years), compared with those with all types of loss-of-function variants (28.5 years) or genomic rearrangements (35.8 years). With the exception of adrenocortical carcinoma, affected children mostly harbored dominant-negative missense pathogenic variants. Among 127 female carriers of pathogenic variants with breast cancer, 31% developed CBC. Receptor status information was available for 40 tumors, which indicated 55% were HER2-positive, and 37% were triple-positive (i.e., ER-positive, PR-positive, and HER2-positive). There was an exceptionally high rate of multiple malignancies (43%) among carriers of pathogenic variants, of which 83% were metachronous. Treatment records were available for 64 carriers who received radiation therapy for treatment of their first tumor; of these, 19 (30%) developed 26 secondary tumors within a radiation field, with a latency of 2 to 26 years (mean, 10.7 y).

Similarly, results of 286 TP53 pathogenic variant–positive individuals in the National Cancer Institute’s LFS Study indicated a cumulative cancer incidence of almost 100% by age 70 years for both males and females.[358] They reported substantial variations by sex, age, and cancer type. Specifically, cumulative cancer incidence reached 50% by age 31 years in females and age 46 years in males, although male risks were higher in childhood and late adulthood. Cumulative cancer incidence by sex for the top four cancers is included in Table 8. Of those with one cancer, 49% developed at least one additional cancer after a median of 10 years. Age-specific risks for developing first and second cancers were comparable.

Table 8. Cumulative Cancer Risks for the Most Common Li-Fraumeni Syndrome (LFS)-Associated Cancersa,b

	Cumulative Cancer Risk by Age 70 Years
aAdapted from Mai et al.[358]
bOther cancers, such as adrenocortical carcinoma, leukemia, and lung bronchoalveolar cancer, have been considered part of the LFS cancer spectrum.[348,350]
Cancer Type	Females (%)	Males (%)
Breast cancer	54	–
Soft tissue sarcoma	15	22
Brain cancer	6	19
Osteosarcoma	5	11

With the increasing use of multigene (panel) tests, it is important to recognize that pathogenic variants in TP53 are unexpectedly being identified in individuals without a family history characteristic of LFS.[359] The clinical significance of finding an isolated TP53 pathogenic variant in an individual or family who does not meet the Chompret criteria is uncertain. Consequently, it remains important to interpret cancer risks and determine optimal management strategies for individuals who are unexpectedly found to have a germline TP53 pathogenic variant, while taking into account their personal and family histories.

One cohort study evaluated 116 individuals with a germline TP53 pathogenic variant yearly at the National Institutes of Health Clinical Center using multimodality screening with and without gadolinium. Baseline screening identified a cancer in eight patients (6.9%) with a false-positive rate of 34.5% for MRI (n = 40).[360] Screening for breast cancer with annual breast MRI is recommended;[97] additional screening for other cancers has been studied and is evolving.[361,362]

PTEN hamartoma tumor syndromes (including Cowden syndrome)

Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (BRRS) are part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome, and approximately 60% of patients with BRRS have an identifiable PTEN pathogenic variant.[363] In addition, PTEN pathogenic variants have been identified in patients with very diverse clinical phenotypes.[364] The term PTEN hamartoma tumor syndromes refers to any patient with a PTEN pathogenic variant, irrespective of clinical presentation.

PTEN functions as a dual-specificity phosphatase that removes phosphate groups from tyrosine, serine, and threonine. Pathogenic variants of PTEN are diverse, including nonsense, missense, frameshift, and splice-site variants. Approximately 40% of variants are found in exon 5, which encodes the phosphatase core motif, and several recurrent pathogenic variants have been observed.[365] Individuals with variants in the 5’ end or within the phosphatase core of PTEN tend to have more organ systems involved.[366]

Operational criteria for the diagnosis of Cowden syndrome have been published and subsequently updated.[367,368] These included major, minor, and pathognomonic criteria consisting of certain mucocutaneous manifestations and adult-onset dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). An updated set of criteria based on a systematic literature review has been suggested [369] and is currently utilized in the National Comprehensive Cancer Network (NCCN) guidelines.[97] Contrary to previous criteria, the authors concluded that there was insufficient evidence for any features to be classified as pathognomonic. With increased utilization of genetic testing, especially the use of multigene panels, clinical criteria for Cowden syndrome will need to be reconciled with the phenotype of individuals with documented germline PTEN pathogenic variants who do not meet these criteria. Until then, whether Cowden syndrome and the other PTEN hamartoma tumor syndromes will be defined clinically or based on the results of genetic testing remains ambiguous. The American College of Medical Genetics and Genomics (ACMG) suggests that referral for genetics consultation be considered for individuals with a personal history of or a first-degree relative with 1) adult-onset Lhermitte-Duclos disease or 2) any three of the major or minor criteria that have been established for the diagnosis of Cowden syndrome.[99] Detailed recommendations, including diagnostic criteriaExit Disclaimer for Cowden syndrome, can be found in the NCCN and ACMG guidelines.[97,99] Additionally, a predictive modelExit Disclaimer that uses clinical criteria to estimate the probability of a PTEN pathogenic variant is available; a cost-effectiveness analysis suggests that germline PTEN testing is cost effective if the probability of a variant is greater than 10%.[370]

Over a 10-year period, the International Cowden Consortium (ICC) prospectively recruited a consecutive series of adult and pediatric patients meeting relaxed ICC criteria for PTEN testing in the United States, Europe, and Asia.[371] Most individuals did not meet the clinical criteria for a diagnosis of Cowden syndrome or BRRS. Of the 3,399 individuals recruited and tested, 295 probands (8.8%) and an additional 73 family members were found to harbor germline PTEN pathogenic variants. In addition to breast, thyroid, and endometrial cancers, the authors concluded that on the basis of cancer risk, melanoma, kidney cancer, and colorectal cancers should be considered part of the cancer spectra arising from germline PTEN pathogenic variants. A second study of approximately 100 patients with a germline PTEN pathogenic variant confirmed these findings and suggested a cumulative cancer risk of 85% by age 70 years.[372]

Although PTEN pathogenic variants, which are estimated to occur in 1 in 200,000 individuals,[367] account for a small fraction of hereditary breast cancer, the characterization of PTEN function will provide valuable insights into the signal pathway and the maintenance of normal cell physiology.[367,373] Lifetime breast cancer risk is estimated to be between 25% and 50% among women with Cowden syndrome.[374] Other studies have reported risks as high as 85%;[371,372,375,376] however, there are concerns regarding selection bias in these studies. As in other forms of hereditary breast cancer, onset is often at a young age and may be bilateral.[377] Lifetime risk of endometrial cancer is estimated to be between 19% and 28%, depending on the cohort studied, with an increased risk of premenopausal onset.[371,372,378] Because of the low prevalence of PTEN pathogenic variants in the population, the proportion of endometrial cancer attributable to Cowden syndrome is small. There are no data that link PTEN pathogenic variants to an increased risk of ovarian cancer. Skin manifestations include multiple trichilemmomas, oral fibromas and papillomas, and acral, palmar, and plantar keratoses. History or observation of the characteristic skin features raises a suspicion of Cowden syndrome. CNS manifestations include macrocephaly, developmental delay, and dysplastic gangliocytomas of the cerebellum.[379,380] (Refer to the PDQ summaries on Genetics of Colorectal Cancer and Genetics of Skin Cancer for more information about PTEN hamartoma tumor syndromes [including Cowden syndrome].)

Diffuse gastric and lobular breast cancer syndrome

The E-cadherin gene CDH1 was first described in 1998 in three Maori families with multiple cases of diffuse gastric cancer (DGC), leading to the designation of hereditary diffuse gastric cancer (HDGC). There have been multiple subsequent reports of an excess of lobular breast cancer in HDGC families.[381] CDH1 is located on chromosome 16q22.1 and encodes the E-cadherin protein, a calcium-dependent homophilic adhesion molecule that plays a key role in cellular adhesion, cell polarity, cell signaling, and maintenance of cellular differentiation and tissue morphology.[382] E-cadherin binds to various catenins to stabilize the cytoplasmic cell adhesion complex and to maintain the E-cadherin interaction with actin filament.[383] Loss of CDH1 can occur as a result of somatic mutations, LOH, or hypermethylation, and can result in dedifferentiation and invasiveness in human cancers.[384,385] Classic histopathologic findings in gastrectomy specimens include in situ signet ring cells and/or pagetoid spread of signet ring cells. Of all gastric cancers, 1% to 3% are attributed to inherited gastric cancer syndromes.[386]

HDGC is an autosomal dominant syndrome associated with poorly differentiated invasive adenocarcinoma of the stomach presenting as linitis plastica. It is a highly penetrant and highly fatal syndrome, with a risk of clinical DGC ranging from 40% to 83%.[381] The risk of lobular breast cancer, which is characterized by small uniform cells that tend to invade in “single files,” is also increased in HDGC. Although invasive lobular breast cancer represents only 10% to 15% of all breast cancers, the lifetime risk of lobular breast cancer in carriers of CDH1 pathogenic variants ranges from 30% to 50%.[383,384] Guidelines for screening for CDH1 vary but include multiple cases of DGC in a family, early age of DGC, or lobular breast cancer in a family with DGC. Approximately 25% of families meeting these criteria are found to have a pathogenic variant in CDH1.[386] CDH1 pathogenic variants have been found in some families with lobular breast cancer but no gastric cancer.[387] The management of individuals with CDH1 pathogenic variants without a family history of gastric cancer is unclear.[387]

Peutz-Jeghers syndrome (PJS)

PJS is an early-onset autosomal dominant disorder characterized by melanocytic macules on the lips, the perioral region, and buccal region; and multiple gastrointestinal polyps, both hamartomatous and adenomatous.[388-390] Germline pathogenic variants in the STK11 gene at chromosome 19p13.3 have been identified in the vast majority of PJS families.[391-395] The most common cancers in PJS are gastrointestinal. However, other organs are at increased risk of developing malignancies. For example, the cumulative risks have been estimated to be 32% to 54% for breast cancer [396-398] and 21% for ovarian cancer (mainly ovarian sex-cord tumors).[396] The risk for pancreatic cancer has been estimated to be more than 100-fold higher than that in the general population.[396] A systematic review found a lifetime cumulative cancer risk, all sites combined, of up to 93% in patients with PJS.[396,399] Table 9 shows the cumulative risk of these tumors.

Females with PJS are also predisposed to the development of cervical adenoma malignum, a rare and very aggressive adenocarcinoma of the cervix.[400] In addition, females with PJS commonly develop benign ovarian sex-cord tumors with annular tubules, whereas males with PJS are predisposed to development of Sertoli-cell testicular tumors;[401] although neither of these two tumor types is malignant, they can cause symptoms related to increased estrogen production.

Although the risk of malignancy appears to be exceedingly high in individuals with PJS based on the published literature, the possibility that selection and referral biases have resulted in overestimates of these risks should be considered.

Table 9. Cumulative Cancer Risks in Peutz-Jeghers Syndrome Up To Specified Agea

Site	Age (y)	Cumulative Risk (%)b	Reference(s)
GI = gastrointestinal.
aReprinted with permission from Macmillan Publishers Ltd: Gastroenterology [399], copyright 2010.
bAll cumulative risks were increased compared with the general population (P < .05), with the exception of cervix and testes.
cGI cancers include colorectal, small intestinal, gastric, esophageal, and pancreatic.
dWesterman et al.: GI cancer does not include pancreatic cancer.[402]
eDid not include adenoma malignum of the cervix or Sertoli cell tumors of the testes.
Any cancer	60–70	37–93	[395-398,402,403]
GI cancerc,d	60–70	38–66	[397,398,402,403]
Gynecological cancer	60–70	13–18	[397,398]
Per origin
Stomach	65	29	[396]
Small bowel	65	13	[396]
Colorectum	65	39	[396,397]
Pancreas	65–70	11–36	[396,397]
Lung	65–70	7–17	[396-398]
Breast	60–70	32–54	[396-398]
Uterus	65	9	[396]
Ovary	65	21	[396]
Cervixe	65	10	[396]
Testese	65	9	[396]

Peutz-Jeghers gene(s)

PJS is caused by pathogenic variants in the STK11 (also called LKB1) tumor suppressor gene located on chromosome 19p13.[392,393] Unlike the adenomas seen in familial adenomatous polyposis, the polyps arising in PJS are hamartomas. Studies of the hamartomatous polyps and cancers of PJS show allelic imbalance (LOH) consistent with the two-hit hypothesis, demonstrating that STK11 is a tumor suppressor gene.[404,405] However, heterozygous STK11 knockout mice develop hamartomas without inactivation of the remaining wild-type allele, suggesting that haploinsufficiency may be sufficient for initial tumor development in PJS.[406] Subsequently, the cancers that develop in STK11 +/- mice do show LOH;[407] indeed, compound mutant mice heterozygous for pathogenic variants in STK11 +/- and homozygous for pathogenic variants in TP53 -/- have accelerated development of both hamartomas and cancers.[408]

Germline variants of the STK11 gene represent a spectrum of nonsense, frameshift, and missense variants, and splice-site variants and large deletions.[391,397]

Approximately 85% of variants are localized to regions of the kinase domain of the expressed protein. No strong genotype-phenotype correlations have been identified.[397] Up to 30% of variants are large deletions involving one or more exons of STK11, underscoring the importance of deletion analysis in suspected cases of PJS.[391]

STK11 has been unequivocally demonstrated to cause PJS. Although earlier estimates using direct DNA sequencing showed a 50% pathogenic variant detection rate in STK11, studies adding techniques to detect large deletions have found pathogenic variants in up to 94% of individuals meeting clinical criteria for PJS.[391,399,409] Given the results of these studies, it is unlikely that other major genes cause PJS.

Clinical management

The high cumulative risk of cancers in PJS has led to the various screening recommendations summarized in the table of Published Recommendations for Diagnosis and Surveillance of Peutz-Jeghers Syndrome (PJS) in the PDQ summary on Genetics of Colorectal Cancer.

PALB2

PALB2 (partner and localizer of BRCA2) interacts with the BRCA2 protein and plays a role in homologous recombination and double-stranded DNA repair. Similar to BRIP1 and BRCA2, biallelic pathogenic variants in PALB2 have also been shown to cause Fanconi anemia.[410]

PALB2 pathogenic variants have been screened for in multiple small studies of familial and early-onset breast cancer in multiple populations.[14,411-428] Pathogenic variant prevalence has ranged from 0.4% to 3.9%. Similar to BRIP1 and CHEK2, there was incomplete segregation of PALB2 pathogenic variants in families with hereditary breast cancer.[411] Among 559 cases with CBC and 565 matched controls with unilateral breast cancer, pathogenic (truncating) PALB2 pathogenic variants were identified in 0.9% of cases and in none of the controls (RR, 5.3; 95% CI, 1.8–13.2).[422]

Data based on 154 families with loss-of-function PALB2 variants suggest that this gene may be an important cause of hereditary breast cancer, with risks that overlap with BRCA2.[429] In this study, analysis of 362 family members from 154 families with PALB2 pathogenic variants indicated that the absolute risk of female breast cancer by age 70 years ranged from 33% (95% CI, 24%–44%) for those with no family history of breast cancer to 58% (95% CI, 50%–66%) for those with two or more FDRs with early-onset breast cancer. Furthermore, among 63 breast cancer cases in which HER2 status was known, 30% had triple-negative disease. An earlier Finnish study reported on a PALB2 founder pathogenic variant (c.1592delT) that confers a 40% risk of breast cancer to age 70 years [412] and is associated with a high incidence (54%) of triple-negative disease and lower survival.[413] Pathogenic variants have been observed in early-onset and familial breast cancer in many populations.[414,415] A large report of 1,824 patients with triple-negative breast cancer unselected for family history, recruited through 12 studies, identified 1.2% with a PALB2 pathogenic variant.[246] (Refer to the BRCA1 pathology section of this summary for more information about this study.)

In a later Polish study of more than 12,529 unselected women with breast cancer and 4,702 controls, PALB2 pathogenic variants were detected in 116 cases (0.93%; 95% CI, 0.76%–1.09%) and 10 controls (0.21%; 95% CI, 0.08%–0.34%), with an OR for breast cancer of 4.39 (95% CI, 2.30–8.37).[430] The study findings confirm a substantially elevated risk of breast cancer (24%–40%) among women with a PALB2 pathogenic variant up to age 75 years. The 5-year cumulative incidence of CBC was 10% among those with a PALB2 pathogenic variant, compared with 17% among those with a BRCA1 pathogenic variant and 3% among those without a variant in either gene. Furthermore, the 10-year survival for women with a PALB2 pathogenic variant and breast cancer was 48% (95% CI, 36.5%–63.2%), compared with 72.0% among those with a BRCA1 pathogenic variant and 74.7% among those without a variant in either gene. Among PALB2 carriers, breast tumors 2 cm or larger had substantially worse outcomes (32.4% 10-year survival), compared with tumors smaller than 2 cm (82.4% 10-year survival). Approximately one-third of those with a PALB2 pathogenic variant had triple-negative breast cancer, and the average age at breast cancer diagnosis was 53.3 years.

Male breast cancer has been observed in PALB2 pathogenic variant–positive breast cancer families.[14,416,429] In a study of 115 male breast cancer cases in which 18 men had BRCA2 pathogenic variants, an additional two men had either a pathogenic or predicted pathogenic PALB2 variant (accounting for about 10% of germline variants in the study and 1%–2% of the total sample).[14] The RR of breast cancer for male carriers of PALB2 pathogenic variants compared with that seen in the general population was estimated to be 8.30 (95% CI, 0.77–88.56; P = .08) in the study of 154 families.[429]

After the identification of PALB2 pathogenic variants in pancreatic tumors and the detection of germline pathogenic variants in 3% of 96 familial pancreatic patients,[431] numerous studies have pointed to a role for PALB2 in pancreatic cancer. PALB2 pathogenic variants were detected in 3.7% of 81 familial pancreatic cancer families [432] and in 2.1% of 94 BRCA1/BRCA2 pathogenic variant–negative breast cancer patients who had either a personal or family history of pancreatic cancer.[433] Two relatively small studies—one of 77 BRCA1/BRCA2 pathogenic variant–negative probands with a personal or family history of pancreatic cancer, one-half of whom were of AJ descent, and another study of 29 Italian pancreatic cancer patients with a personal or family history of breast or ovarian cancer—failed to detect any PALB2 pathogenic variants.[434,435] A sixfold increase in pancreatic cancer was observed in the relatives of 33 BRCA1/BRCA2-negative, PALB2 pathogenic variant–positive breast cancer probands.[416]

Overall, the observed prevalence of PALB2 pathogenic variants in familial breast cancer varied depending on ascertainment relative to personal and family history of pancreatic and ovarian cancers, but in all studies, the observed pathogenic variant rate was lower than 4%. Data suggest that the RR of breast cancer may overlap with that of BRCA2, particularly in those with a strong family history; thus, it remains important to refine cancer risk estimates in larger studies. Furthermore, the risk of other cancers (e.g., pancreatic) is poorly defined. Given the low PALB2 pathogenic variant prevalence in the population, additional data are needed to define best candidates for testing and appropriate management.

De Novo Pathogenic Variant Rate

Until the 1990s, the diagnosis of genetically inherited breast and ovarian cancer syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous pathogenic variant rate (de novo pathogenic variant rate) in these populations. Interestingly, PJS, PTEN hamartoma syndromes, and LFS are all thought to have high rates of spontaneous pathogenic variants, in the 10% to 30% range,[436-439] while estimates of de novo pathogenic variants in the BRCA genes are thought to be low, primarily on the basis of the few case reports published.[440-448] Additionally, there has been only one case series of breast cancer patients who were tested for BRCA pathogenic variants in which a de novo variant was identified. Specifically, in this study of 193 patients with sporadic breast cancer, 17 pathogenic variants were detected, one of which was confirmed to be a de novo pathogenic variant.[440] As such, the de novo pathogenic variant rate appears to be low and fall into the 5% or less range, based on the limited studies performed.[440-448] Similarly, estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[449-451] However, these estimates of spontaneous pathogenic variant rates in the BRCA genes and Lynch syndrome genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%),[452-454] making the de novo pathogenic variant rate for these genes relatively low.

References

1. Phipps RF, Perry PM: Familial breast cancer. Postgrad Med J 64 (757): 847-9, 1988. [PUBMED Abstract]
2. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994. [PUBMED Abstract]
3. Newman B, Austin MA, Lee M, et al.: Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proceedings of the National Academy of Sciences 85 (9): 3044-48, 1988.
4. Hall JM, Lee MK, Newman B, et al.: Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250 (4988): 1684-9, 1990. [PUBMED Abstract]
5. Narod SA, Feunteun J, Lynch HT, et al.: Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338 (8759): 82-3, 1991. [PUBMED Abstract]
6. Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002. [PUBMED Abstract]
7. Thompson D, Easton DF; Breast Cancer Linkage Consortium: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002. [PUBMED Abstract]
8. Risch HA, McLaughlin JR, Cole DE, et al.: Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst 98 (23): 1694-706, 2006. [PUBMED Abstract]
9. Tai YC, Domchek S, Parmigiani G, et al.: Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99 (23): 1811-4, 2007. [PUBMED Abstract]
10. Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994. [PUBMED Abstract]
11. Gayther SA, Mangion J, Russell P, et al.: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15 (1): 103-5, 1997. [PUBMED Abstract]
12. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999. [PUBMED Abstract]
13. Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004. [PUBMED Abstract]
14. Ding YC, Steele L, Kuan CJ, et al.: Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat 126 (3): 771-8, 2011. [PUBMED Abstract]
15. Tonin P, Weber B, Offit K, et al.: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2 (11): 1179-83, 1996. [PUBMED Abstract]
16. Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993. [PUBMED Abstract]
17. Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108 (2): 171-82, 2002. [PUBMED Abstract]
18. Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 4 (9): 665-76, 2004. [PUBMED Abstract]
19. An Open Access On-Line Breast Cancer Mutation Data Base [Database]. Bethesda, Md: National Human Genome Research Institute, 2002. Available online. Last accessed June 07, 2019.
20. Ford D, Easton DF, Peto J: Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57 (6): 1457-62, 1995. [PUBMED Abstract]
21. Whittemore AS, Gong G, John EM, et al.: Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic Whites. Cancer Epidemiol Biomarkers Prev 13 (12): 2078-83, 2004. [PUBMED Abstract]
22. Eng C, Brody LC, Wagner TM, et al.: Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1. J Med Genet 38 (12): 824-33, 2001. [PUBMED Abstract]
23. Unger MA, Nathanson KL, Calzone K, et al.: Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing. Am J Hum Genet 67 (4): 841-50, 2000. [PUBMED Abstract]
24. Walsh T, Casadei S, Coats KH, et al.: Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295 (12): 1379-88, 2006. [PUBMED Abstract]
25. Palma MD, Domchek SM, Stopfer J, et al.: The relative contribution of point mutations and genomic rearrangements in BRCA1 and BRCA2 in high-risk breast cancer families. Cancer Res 68 (17): 7006-14, 2008. [PUBMED Abstract]
26. Stadler ZK, Saloustros E, Hansen NA, et al.: Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat 123 (2): 581-5, 2010. [PUBMED Abstract]
27. Judkins T, Rosenthal E, Arnell C, et al.: Clinical significance of large rearrangements in BRCA1 and BRCA2. Cancer 118 (21): 5210-6, 2012. [PUBMED Abstract]
28. Shannon KM, Rodgers LH, Chan-Smutko G, et al.: Which individuals undergoing BRACAnalysis need BART testing? Cancer Genet 204 (8): 416-22, 2011. [PUBMED Abstract]
29. Jackson SA, Davis AA, Li J, et al.: Characteristics of individuals with breast cancer rearrangements in BRCA1 and BRCA2. Cancer 120 (10): 1557-64, 2014. [PUBMED Abstract]
30. Weitzel JN, Lagos VI, Herzog JS, et al.: Evidence for common ancestral origin of a recurring BRCA1 genomic rearrangement identified in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 16 (8): 1615-20, 2007. [PUBMED Abstract]
31. Plon SE, Eccles DM, Easton D, et al.: Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29 (11): 1282-91, 2008. [PUBMED Abstract]
32. Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002. [PUBMED Abstract]
33. Nanda R, Schumm LP, Cummings S, et al.: Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294 (15): 1925-33, 2005. [PUBMED Abstract]
34. Hall MJ, Reid JE, Burbidge LA, et al.: BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115 (10): 2222-33, 2009. [PUBMED Abstract]
35. Szabo C, Masiello A, Ryan JF, et al.: The breast cancer information core: database design, structure, and scope. Hum Mutat 16 (2): 123-31, 2000. [PUBMED Abstract]
36. Spurdle AB, Healey S, Devereau A, et al.: ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat 33 (1): 2-7, 2012. [PUBMED Abstract]
37. Goldgar DE, Easton DF, Deffenbaugh AM, et al.: Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75 (4): 535-44, 2004. [PUBMED Abstract]
38. Thompson D, Easton DF, Goldgar DE: A full-likelihood method for the evaluation of causality of sequence variants from family data. Am J Hum Genet 73 (3): 652-5, 2003. [PUBMED Abstract]
39. Spearman AD, Sweet K, Zhou XP, et al.: Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. J Clin Oncol 26 (33): 5393-400, 2008. [PUBMED Abstract]
40. Gómez García EB, Oosterwijk JC, Timmermans M, et al.: A method to assess the clinical significance of unclassified variants in the BRCA1 and BRCA2 genes based on cancer family history. Breast Cancer Res 11 (1): R8, 2009. [PUBMED Abstract]
41. Goldgar DE, Easton DF, Byrnes GB, et al.: Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat 29 (11): 1265-72, 2008. [PUBMED Abstract]
42. Fleming MA, Potter JD, Ramirez CJ, et al.: Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc Natl Acad Sci U S A 100 (3): 1151-6, 2003. [PUBMED Abstract]
43. Tavtigian SV, Deffenbaugh AM, Yin L, et al.: Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43 (4): 295-305, 2006. [PUBMED Abstract]
44. Mirkovic N, Marti-Renom MA, Weber BL, et al.: Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition. Cancer Res 64 (11): 3790-7, 2004. [PUBMED Abstract]
45. Abkevich V, Zharkikh A, Deffenbaugh AM, et al.: Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41 (7): 492-507, 2004. [PUBMED Abstract]
46. Couch FJ, Rasmussen LJ, Hofstra R, et al.: Assessment of functional effects of unclassified genetic variants. Hum Mutat 29 (11): 1314-26, 2008. [PUBMED Abstract]
47. Chenevix-Trench G, Healey S, Lakhani S, et al.: Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66 (4): 2019-27, 2006. [PUBMED Abstract]
48. Ostrow KL, McGuire V, Whittemore AS, et al.: The effects of BRCA1 missense variants V1804D and M1628T on transcriptional activity. Cancer Genet Cytogenet 153 (2): 177-80, 2004. [PUBMED Abstract]
49. Wu K, Hinson SR, Ohashi A, et al.: Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res 65 (2): 417-26, 2005. [PUBMED Abstract]
50. Weitzel JN, Lagos V, Blazer KR, et al.: Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer Epidemiol Biomarkers Prev 14 (7): 1666-71, 2005. [PUBMED Abstract]
51. Mefford HC, Baumbach L, Panguluri RC, et al.: Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet 65 (2): 575-8, 1999. [PUBMED Abstract]
52. Rosenthal E, Moyes K, Arnell C, et al.: Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry. Breast Cancer Res Treat 149 (1): 223-7, 2015. [PUBMED Abstract]
53. Frey MK, Kopparam RV, Ni Zhou Z, et al.: Prevalence of nonfounder BRCA1/2 mutations in Ashkenazi Jewish patients presenting for genetic testing at a hereditary breast and ovarian cancer center. Cancer 125 (5): 690-697, 2019. [PUBMED Abstract]
54. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer 83 (10): 1301-8, 2000. [PUBMED Abstract]
55. Papelard H, de Bock GH, van Eijk R, et al.: Prevalence of BRCA1 in a hospital-based population of Dutch breast cancer patients. Br J Cancer 83 (6): 719-24, 2000. [PUBMED Abstract]
56. Loman N, Johannsson O, Kristoffersson U, et al.: Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 93 (16): 1215-23, 2001. [PUBMED Abstract]
57. Malone KE, Daling JR, Doody DR, et al.: Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Res 66 (16): 8297-308, 2006. [PUBMED Abstract]
58. Newman B, Mu H, Butler LM, et al.: Frequency of breast cancer attributable to BRCA1 in a population-based series of American women. JAMA 279 (12): 915-21, 1998. [PUBMED Abstract]
59. Basham VM, Lipscombe JM, Ward JM, et al.: BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4 (1): R2, 2002. [PUBMED Abstract]
60. Risch HA, McLaughlin JR, Cole DE, et al.: Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68 (3): 700-10, 2001. [PUBMED Abstract]
61. Rubin SC, Blackwood MA, Bandera C, et al.: BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am J Obstet Gynecol 178 (4): 670-7, 1998. [PUBMED Abstract]
62. Pal T, Permuth-Wey J, Betts JA, et al.: BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer 104 (12): 2807-16, 2005. [PUBMED Abstract]
63. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997. [PUBMED Abstract]
64. Gabai-Kapara E, Lahad A, Kaufman B, et al.: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A 111 (39): 14205-10, 2014. [PUBMED Abstract]
65. Metcalfe KA, Poll A, Royer R, et al.: Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women. J Clin Oncol 28 (3): 387-91, 2010. [PUBMED Abstract]
66. King MC, Marks JH, Mandell JB, et al.: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302 (5645): 643-6, 2003. [PUBMED Abstract]
67. Gershoni-Baruch R, Dagan E, Fried G, et al.: Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer. Eur J Cancer 36 (8): 983-6, 2000. [PUBMED Abstract]
68. Hodgson SV, Heap E, Cameron J, et al.: Risk factors for detecting germline BRCA1 and BRCA2 founder mutations in Ashkenazi Jewish women with breast or ovarian cancer. J Med Genet 36 (5): 369-73, 1999. [PUBMED Abstract]
69. Struewing JP, Coriaty ZM, Ron E, et al.: Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet 65 (6): 1800-2, 1999. [PUBMED Abstract]
70. Hirsh-Yechezkel G, Chetrit A, Lubin F, et al.: Population attributes affecting the prevalence of BRCA mutation carriers in epithelial ovarian cancer cases in Israel. Gynecol Oncol 89 (3): 494-8, 2003. [PUBMED Abstract]
71. Moslehi R, Chu W, Karlan B, et al.: BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. Am J Hum Genet 66 (4): 1259-72, 2000. [PUBMED Abstract]
72. Levine DA, Argenta PA, Yee CJ, et al.: Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J Clin Oncol 21 (22): 4222-7, 2003. [PUBMED Abstract]
73. John EM, Miron A, Gong G, et al.: Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA 298 (24): 2869-76, 2007. [PUBMED Abstract]
74. Weitzel JN, Clague J, Martir-Negron A, et al.: Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network. J Clin Oncol 31 (2): 210-6, 2013. [PUBMED Abstract]
75. Torres-Mejía G, Royer R, Llacuachaqui M, et al.: Recurrent BRCA1 and BRCA2 mutations in Mexican women with breast cancer. Cancer Epidemiol Biomarkers Prev 24 (3): 498-505, 2015. [PUBMED Abstract]
76. Vicus D, Finch A, Cass I, et al.: Prevalence of BRCA1 and BRCA2 germ line mutations among women with carcinoma of the fallopian tube. Gynecol Oncol 118 (3): 299-302, 2010. [PUBMED Abstract]
77. Aziz S, Kuperstein G, Rosen B, et al.: A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol 80 (3): 341-5, 2001. [PUBMED Abstract]
78. Manchanda R, Loggenberg K, Sanderson S, et al.: Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial. J Natl Cancer Inst 107 (1): 379, 2015. [PUBMED Abstract]
79. Manchanda R, Legood R, Burnell M, et al.: Cost-effectiveness of population screening for BRCA mutations in Ashkenazi jewish women compared with family history-based testing. J Natl Cancer Inst 107 (1): 380, 2015. [PUBMED Abstract]
80. Metcalfe KA, Poll A, Royer R, et al.: A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing. Br J Cancer 109 (3): 777-9, 2013. [PUBMED Abstract]
81. Manchanda R, Patel S, Antoniou AC, et al.: Cost-effectiveness of population based BRCA testing with varying Ashkenazi Jewish ancestry. Am J Obstet Gynecol 217 (5): 578.e1-578.e12, 2017. [PUBMED Abstract]
82. Manchanda R, Patel S, Gordeev VS, et al.: Cost-effectiveness of Population-Based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 Mutation Testing in Unselected General Population Women. J Natl Cancer Inst 110 (7): 714-725, 2018. [PUBMED Abstract]
83. Couch FJ, DeShano ML, Blackwood MA, et al.: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336 (20): 1409-15, 1997. [PUBMED Abstract]
84. Shattuck-Eidens D, Oliphant A, McClure M, et al.: BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing. JAMA 278 (15): 1242-50, 1997. [PUBMED Abstract]
85. Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994. [PUBMED Abstract]
86. Frank TS, Manley SA, Olopade OI, et al.: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 16 (7): 2417-25, 1998. [PUBMED Abstract]
87. Chang-Claude J, Dong J, Schmidt S, et al.: Using gene carrier probability to select high risk families for identifying germline mutations in breast cancer susceptibility genes. J Med Genet 35 (2): 116-21, 1998. [PUBMED Abstract]
88. Couch FJ, Hartmann LC: BRCA1 testing--advances and retreats. JAMA 279 (12): 955-7, 1998. [PUBMED Abstract]
89. Parmigiani G, Berry D, Aguilar O: Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62 (1): 145-58, 1998. [PUBMED Abstract]
90. Ready K, Litton JK, Arun BK: Clinical application of breast cancer risk assessment models. Future Oncol 6 (3): 355-65, 2010. [PUBMED Abstract]
91. Amir E, Freedman OC, Seruga B, et al.: Assessing women at high risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst 102 (10): 680-91, 2010. [PUBMED Abstract]
92. Lakhani SR, Reis-Filho JS, Fulford L, et al.: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11 (14): 5175-80, 2005. [PUBMED Abstract]
93. Kwon JS, Gutierrez-Barrera AM, Young D, et al.: Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol 28 (27): 4214-20, 2010. [PUBMED Abstract]
94. Young SR, Pilarski RT, Donenberg T, et al.: The prevalence of BRCA1 mutations among young women with triple-negative breast cancer. BMC Cancer 9: 86, 2009. [PUBMED Abstract]
95. Greenup R, Buchanan A, Lorizio W, et al.: Prevalence of BRCA mutations among women with triple-negative breast cancer (TNBC) in a genetic counseling cohort. Ann Surg Oncol 20 (10): 3254-8, 2013. [PUBMED Abstract]
96. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
97. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
98. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994. [PUBMED Abstract]
99. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
100. Owens DK, Davidson KW, Krist AH, et al.: Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 322 (7): 652-665, 2019. [PUBMED Abstract]
101. Lancaster JM, Powell CB, Kauff ND, et al.: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 107 (2): 159-62, 2007. [PUBMED Abstract]
102. Evans DG, Eccles DM, Rahman N, et al.: A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41 (6): 474-80, 2004. [PUBMED Abstract]
103. Apicella C, Dowty JG, Dite GS, et al.: Validation study of the LAMBDA model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women. Clin Genet 72 (2): 87-97, 2007. [PUBMED Abstract]
104. Antoniou AC, Pharoah PP, Smith P, et al.: The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer 91 (8): 1580-90, 2004. [PUBMED Abstract]
105. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995. [PUBMED Abstract]
106. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996. [PUBMED Abstract]
107. Warner E, Foulkes W, Goodwin P, et al.: Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst 91 (14): 1241-7, 1999. [PUBMED Abstract]
108. Euhus DM, Smith KC, Robinson L, et al.: Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 94 (11): 844-51, 2002. [PUBMED Abstract]
109. de la Hoya M, Díez O, Pérez-Segura P, et al.: Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics. J Med Genet 40 (7): 503-10, 2003. [PUBMED Abstract]
110. Katki HA: Incorporating medical interventions into carrier probability estimation for genetic counseling. BMC Med Genet 8: 13, 2007. [PUBMED Abstract]
111. Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007. [PUBMED Abstract]
112. Jervis S, Song H, Lee A, et al.: A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects. J Med Genet 52 (7): 465-75, 2015. [PUBMED Abstract]
113. Oros KK, Ghadirian P, Maugard CM, et al.: Application of BRCA1 and BRCA2 mutation carrier prediction models in breast and/or ovarian cancer families of French Canadian descent. Clin Genet 70 (4): 320-9, 2006. [PUBMED Abstract]
114. Vogel KJ, Atchley DP, Erlichman J, et al.: BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model. J Clin Oncol 25 (29): 4635-41, 2007. [PUBMED Abstract]
115. Kurian AW, Gong GD, John EM, et al.: Performance of prediction models for BRCA mutation carriage in three racial/ethnic groups: findings from the Northern California Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 18 (4): 1084-91, 2009. [PUBMED Abstract]
116. Kurian AW, Gong GD, Chun NM, et al.: Performance of BRCA1/2 mutation prediction models in Asian Americans. J Clin Oncol 26 (29): 4752-8, 2008. [PUBMED Abstract]
117. Berry DA, Parmigiani G, Sanchez J, et al.: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst 89 (3): 227-38, 1997. [PUBMED Abstract]
118. Barcenas CH, Hosain GM, Arun B, et al.: Assessing BRCA carrier probabilities in extended families. J Clin Oncol 24 (3): 354-60, 2006. [PUBMED Abstract]
119. Kang HH, Williams R, Leary J, et al.: Evaluation of models to predict BRCA germline mutations. Br J Cancer 95 (7): 914-20, 2006. [PUBMED Abstract]
120. Antoniou AC, Hardy R, Walker L, et al.: Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics. J Med Genet 45 (7): 425-31, 2008. [PUBMED Abstract]
121. Fischer C, Kuchenbäcker K, Engel C, et al.: Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium. J Med Genet 50 (6): 360-7, 2013. [PUBMED Abstract]
122. Biswas S, Tankhiwale N, Blackford A, et al.: Assessing the added value of breast tumor markers in genetic risk prediction model BRCAPRO. Breast Cancer Res Treat 133 (1): 347-55, 2012. [PUBMED Abstract]
123. Tai YC, Chen S, Parmigiani G, et al.: Incorporating tumor immunohistochemical markers in BRCA1 and BRCA2 carrier prediction. Breast Cancer Res 10 (2): 401, 2008. [PUBMED Abstract]
124. Tyrer J, Duffy SW, Cuzick J: A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23 (7): 1111-30, 2004. [PUBMED Abstract]
125. Ready KJ, Vogel KJ, Atchley DP, et al.: Accuracy of the BRCAPRO model among women with bilateral breast cancer. Cancer 115 (4): 725-30, 2009. [PUBMED Abstract]
126. Huo D, Senie RT, Daly M, et al.: Prediction of BRCA Mutations Using the BRCAPRO Model in Clinic-Based African American, Hispanic, and Other Minority Families in the United States. J Clin Oncol 27 (8): 1184-90, 2009. [PUBMED Abstract]
127. Daniels MS, Babb SA, King RH, et al.: Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high-grade serous ovarian cancer by BRCAPRO: a multi-institution study. J Clin Oncol 32 (12): 1249-55, 2014. [PUBMED Abstract]
128. Antoniou A, Pharoah PD, Narod S, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72 (5): 1117-30, 2003. [PUBMED Abstract]
129. Chen S, Parmigiani G: Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25 (11): 1329-33, 2007. [PUBMED Abstract]
130. Kuchenbaecker KB, Hopper JL, Barnes DR, et al.: Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 317 (23): 2402-2416, 2017. [PUBMED Abstract]
131. Antoniou AC, Pharoah PD, Narod S, et al.: Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet 42 (7): 602-3, 2005. [PUBMED Abstract]
132. Finkelman BS, Rubinstein WS, Friedman S, et al.: Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol 30 (12): 1321-8, 2012. [PUBMED Abstract]
133. Ramus SJ, Song H, Dicks E, et al.: Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst 107 (11): , 2015. [PUBMED Abstract]
134. Song H, Dicks E, Ramus SJ, et al.: Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol 33 (26): 2901-7, 2015. [PUBMED Abstract]
135. Rebbeck TR, Mitra N, Wan F, et al.: Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313 (13): 1347-61, 2015. [PUBMED Abstract]
136. Rebbeck TR, Friebel TM, Mitra N, et al.: Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women. Breast Cancer Res 18 (1): 112, 2016. [PUBMED Abstract]
137. Guindalini RS, Song A, Fackenthal JD, et al.: Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect. Cancer 122 (12): 1913-20, 2016. [PUBMED Abstract]
138. Agranat S, Baris H, Kedar I, et al.: Earlier Age of Breast Cancer Onset in Israeli BRCA Carriers-Is it a Real Phenomenon? Breast J 22 (6): 662-666, 2016. [PUBMED Abstract]
139. Litton JK, Ready K, Chen H, et al.: Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer 118 (2): 321-5, 2012. [PUBMED Abstract]
140. Wang WW, Spurdle AB, Kolachana P, et al.: A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers. Cancer Epidemiol Biomarkers Prev 10 (9): 955-60, 2001. [PUBMED Abstract]
141. Levy-Lahad E, Lahad A, Eisenberg S, et al.: A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A 98 (6): 3232-6, 2001. [PUBMED Abstract]
142. Narod SA: Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2 (2): 113-23, 2002. [PUBMED Abstract]
143. Kramer JL, Velazquez IA, Chen BE, et al.: Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol 23 (34): 8629-35, 2005. [PUBMED Abstract]
144. Antoniou AC, Spurdle AB, Sinilnikova OM, et al.: Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet 82 (4): 937-48, 2008. [PUBMED Abstract]
145. Iodice S, Barile M, Rotmensz N, et al.: Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer 46 (12): 2275-84, 2010. [PUBMED Abstract]
146. Antoniou AC, Rookus M, Andrieu N, et al.: Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 18 (2): 601-10, 2009. [PUBMED Abstract]
147. Milne RL, Osorio A, Ramón y Cajal T, et al.: Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119 (1): 221-32, 2010. [PUBMED Abstract]
148. Friedman E, Kotsopoulos J, Lubinski J, et al.: Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 8 (2): R15, 2006. [PUBMED Abstract]
149. Jernström H, Lubinski J, Lynch HT, et al.: Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96 (14): 1094-8, 2004. [PUBMED Abstract]
150. Breast Cancer Family Registry, Kathleen Cuningham Consortium for Research into Familial Breast Cancer (Australasia), Ontario Cancer Genetics Network (Canada): Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years. Breast Cancer Res Treat 109 (1): 67-75, 2008. [PUBMED Abstract]
151. Antoniou AC, Beesley J, McGuffog L, et al.: Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction. Cancer Res 70 (23): 9742-54, 2010. [PUBMED Abstract]
152. Ramus SJ, Kartsonaki C, Gayther SA, et al.: Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 103 (2): 105-16, 2011. [PUBMED Abstract]
153. Milne RL, Antoniou AC: Genetic modifiers of cancer risk for BRCA1 and BRCA2 mutation carriers. Ann Oncol 22 (Suppl 1): i11-7, 2011. [PUBMED Abstract]
154. Graeser MK, Engel C, Rhiem K, et al.: Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27 (35): 5887-92, 2009. [PUBMED Abstract]
155. Malone KE, Begg CB, Haile RW, et al.: Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol 28 (14): 2404-10, 2010. [PUBMED Abstract]
156. van der Kolk DM, de Bock GH, Leegte BK, et al.: Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. Breast Cancer Res Treat 124 (3): 643-51, 2010. [PUBMED Abstract]
157. Metcalfe K, Gershman S, Lynch HT, et al.: Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 104 (9): 1384-92, 2011. [PUBMED Abstract]
158. Molina-Montes E, Pérez-Nevot B, Pollán M, et al.: Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: A systematic review and meta-analysis. Breast 23 (6): 721-42, 2014. [PUBMED Abstract]
159. Basu NN, Ingham S, Hodson J, et al.: Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis. Fam Cancer 14 (4): 531-8, 2015. [PUBMED Abstract]
160. van den Broek AJ, van 't Veer LJ, Hooning MJ, et al.: Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers. J Clin Oncol 34 (5): 409-18, 2016. [PUBMED Abstract]
161. Pierce LJ, Phillips KA, Griffith KA, et al.: Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat 121 (2): 389-98, 2010. [PUBMED Abstract]
162. Domchek SM, Jhaveri K, Patil S, et al.: Risk of metachronous breast cancer after BRCA mutation-associated ovarian cancer. Cancer 119 (7): 1344-8, 2013. [PUBMED Abstract]
163. Vencken PM, Kriege M, Hooning M, et al.: The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: Implications for counseling. Cancer 119 (5): 955-62, 2013. [PUBMED Abstract]
164. Gangi A, Cass I, Paik D, et al.: Breast cancer following ovarian cancer in BRCA mutation carriers. JAMA Surg 149 (12): 1306-13, 2014. [PUBMED Abstract]
165. McGee J, Giannakeas V, Karlan B, et al.: Risk of breast cancer after a diagnosis of ovarian cancer in BRCA mutation carriers: Is preventive mastectomy warranted? Gynecol Oncol 145 (2): 346-351, 2017. [PUBMED Abstract]
166. Casey MJ, Synder C, Bewtra C, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecol Oncol 97 (2): 457-67, 2005. [PUBMED Abstract]
167. Finch A, Beiner M, Lubinski J, et al.: Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA 296 (2): 185-92, 2006. [PUBMED Abstract]
168. Evans DG, Susnerwala I, Dawson J, et al.: Risk of breast cancer in male BRCA2 carriers. J Med Genet 47 (10): 710-1, 2010. [PUBMED Abstract]
169. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003. [PUBMED Abstract]
170. Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003. [PUBMED Abstract]
171. van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al.: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42 (9): 711-9, 2005. [PUBMED Abstract]
172. Mersch J, Jackson MA, Park M, et al.: Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121 (2): 269-75, 2015. [PUBMED Abstract]
173. Mitra A, Fisher C, Foster CS, et al.: Prostate cancer in male BRCA1 and BRCA2 mutation carriers has a more aggressive phenotype. Br J Cancer 98 (2): 502-7, 2008. [PUBMED Abstract]
174. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007. [PUBMED Abstract]
175. Agalliu I, Gern R, Leanza S, et al.: Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res 15 (3): 1112-20, 2009. [PUBMED Abstract]
176. Narod SA, Neuhausen S, Vichodez G, et al.: Rapid progression of prostate cancer in men with a BRCA2 mutation. Br J Cancer 99 (2): 371-4, 2008. [PUBMED Abstract]
177. Edwards SM, Evans DG, Hope Q, et al.: Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer 103 (6): 918-24, 2010. [PUBMED Abstract]
178. Gallagher DJ, Gaudet MM, Pal P, et al.: Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res 16 (7): 2115-21, 2010. [PUBMED Abstract]
179. Couch FJ, Johnson MR, Rabe KG, et al.: The prevalence of BRCA2 mutations in familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev 16 (2): 342-6, 2007. [PUBMED Abstract]
180. Hahn SA, Greenhalf B, Ellis I, et al.: BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95 (3): 214-21, 2003. [PUBMED Abstract]
181. Murphy KM, Brune KA, Griffin C, et al.: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 62 (13): 3789-93, 2002. [PUBMED Abstract]
182. Real FX, Malats N, Lesca G, et al.: Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancer. Gut 50 (5): 653-7, 2002. [PUBMED Abstract]
183. Dagan E: Predominant Ashkenazi BRCA1/2 mutations in families with pancreatic cancer. Genet Test 12 (2): 267-71, 2008. [PUBMED Abstract]
184. Goggins M, Schutte M, Lu J, et al.: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56 (23): 5360-4, 1996. [PUBMED Abstract]
185. Lal G, Liu G, Schmocker B, et al.: Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations. Cancer Res 60 (2): 409-16, 2000. [PUBMED Abstract]
186. Ozçelik H, Schmocker B, Di Nicola N, et al.: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 16 (1): 17-8, 1997. [PUBMED Abstract]
187. Ferrone CR, Levine DA, Tang LH, et al.: BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 27 (3): 433-8, 2009. [PUBMED Abstract]
188. National Cancer Institute: DevCan: Probability of Developing or Dying of Cancer Software. Version 6.7.7. Bethesda, Md: Division of Cancer Control & Population Sciences, National Cancer Institute, 2017. Available online with free registration. Last accessed June 10, 2019.
189. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994. [PUBMED Abstract]
190. Anton-Culver H, Cohen PF, Gildea ME, et al.: Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer. Eur J Cancer 36 (10): 1200-8, 2000. [PUBMED Abstract]
191. Peelen T, de Leeuw W, van Lent K, et al.: Genetic analysis of a breast-ovarian cancer family, with 7 cases of colorectal cancer linked to BRCA1, fails to support a role for BRCA1 in colorectal tumorigenesis. Int J Cancer 88 (5): 778-82, 2000. [PUBMED Abstract]
192. Berman DB, Costalas J, Schultz DC, et al.: A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 56 (15): 3409-14, 1996. [PUBMED Abstract]
193. Aretini P, D'Andrea E, Pasini B, et al.: Different expressivity of BRCA1 and BRCA2: analysis of 179 Italian pedigrees with identified mutation. Breast Cancer Res Treat 81 (1): 71-9, 2003. [PUBMED Abstract]
194. Kirchhoff T, Satagopan JM, Kauff ND, et al.: Frequency of BRCA1 and BRCA2 mutations in unselected Ashkenazi Jewish patients with colorectal cancer. J Natl Cancer Inst 96 (1): 68-70, 2004. [PUBMED Abstract]
195. Niell BL, Rennert G, Bonner JD, et al.: BRCA1 and BRCA2 founder mutations and the risk of colorectal cancer. J Natl Cancer Inst 96 (1): 15-21, 2004. [PUBMED Abstract]
196. Chen-Shtoyerman R, Figer A, Fidder HH, et al.: The frequency of the predominant Jewish mutations in BRCA1 and BRCA2 in unselected Ashkenazi colorectal cancer patients. Br J Cancer 84 (4): 475-7, 2001. [PUBMED Abstract]
197. Levine DA, Lin O, Barakat RR, et al.: Risk of endometrial carcinoma associated with BRCA mutation. Gynecol Oncol 80 (3): 395-8, 2001. [PUBMED Abstract]
198. Goshen R, Chu W, Elit L, et al.: Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome? Gynecol Oncol 79 (3): 477-81, 2000. [PUBMED Abstract]
199. Smith A, Moran A, Boyd MC, et al.: Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 44 (1): 10-15, 2007. [PUBMED Abstract]
200. Goldgar D, Venne V, Conner T, et al.: BRCA phenocopies or ascertainment bias? J Med Genet 44 (8): e86; author reply e88, 2007. [PUBMED Abstract]
201. Eisinger F: Phenocopies: actual risk or self-fulfilling prophecy? J Med Genet 44 (8): e87; author reply e88, 2007. [PUBMED Abstract]
202. Sasieni P: Phenocopies in families seen by cancer geneticists. J Med Genet 44 (6): e82, 2007. [PUBMED Abstract]
203. Tilanus-Linthorst MM: No screening yet after a negative test for the family mutation. J Med Genet 44 (5): e79, 2007. [PUBMED Abstract]
204. Katki HA, Gail MH, Greene MH: Breast-cancer risk in BRCA-mutation-negative women from BRCA-mutation-positive families. Lancet Oncol 8 (12): 1042-3, 2007. [PUBMED Abstract]
205. Raskin L, Lejbkowicz F, Barnett-Griness O, et al.: BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev 18 (5): 1617-23, 2009. [PUBMED Abstract]
206. Gronwald J, Cybulski C, Lubinski J, et al.: Phenocopies in breast cancer 1 (BRCA1) families: implications for genetic counselling. J Med Genet 44 (4): e76, 2007. [PUBMED Abstract]
207. Rowan E, Poll A, Narod SA: A prospective study of breast cancer risk in relatives of BRCA1/BRCA2 mutation carriers. J Med Genet 44 (8): e89; author reply e88, 2007. [PUBMED Abstract]
208. Vos JR, de Bock GH, Teixeira N, et al.: Proven non-carriers in BRCA families have an earlier age of onset of breast cancer. Eur J Cancer 49 (9): 2101-6, 2013. [PUBMED Abstract]
209. Domchek SM, Gaudet MM, Stopfer JE, et al.: Breast cancer risks in individuals testing negative for a known family mutation in BRCA1 or BRCA2. Breast Cancer Res Treat 119 (2): 409-14, 2010. [PUBMED Abstract]
210. Korde LA, Mueller CM, Loud JT, et al.: No evidence of excess breast cancer risk among mutation-negative women from BRCA mutation-positive families. Breast Cancer Res Treat 125 (1): 169-73, 2011. [PUBMED Abstract]
211. Kurian AW, Gong GD, John EM, et al.: Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: findings from the Breast Cancer Family Registry. J Clin Oncol 29 (34): 4505-9, 2011. [PUBMED Abstract]
212. Harvey SL, Milne RL, McLachlan SA, et al.: Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families. Breast Cancer Res Treat 130 (3): 1057-61, 2011. [PUBMED Abstract]
213. Kauff ND, Mitra N, Robson ME, et al.: Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families. J Natl Cancer Inst 97 (18): 1382-4, 2005. [PUBMED Abstract]
214. Lee JS, John EM, McGuire V, et al.: Breast and ovarian cancer in relatives of cancer patients, with and without BRCA mutations. Cancer Epidemiol Biomarkers Prev 15 (2): 359-63, 2006. [PUBMED Abstract]
215. Metcalfe KA, Finch A, Poll A, et al.: Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation. Br J Cancer 100 (2): 421-5, 2009. [PUBMED Abstract]
216. Liede A, Karlan BY, Baldwin RL, et al.: Cancer incidence in a population of Jewish women at risk of ovarian cancer. J Clin Oncol 20 (6): 1570-7, 2002. [PUBMED Abstract]
217. Ingham SL, Warwick J, Buchan I, et al.: Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2. J Med Genet 50 (6): 368-72, 2013. [PUBMED Abstract]
218. Barnes DR, Antoniou AC: Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers. J Intern Med 271 (4): 331-43, 2012. [PUBMED Abstract]
219. Chenevix-Trench G, Milne RL, Antoniou AC, et al.: An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9 (2): 104, 2007. [PUBMED Abstract]
220. Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998. [PUBMED Abstract]
221. Thompson D, Easton D; Breast Cancer Linkage Consortium: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001. [PUBMED Abstract]
222. Thompson D, Easton D; Breast Cancer Linkage Consortium: Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomarkers Prev 11 (4): 329-36, 2002. [PUBMED Abstract]
223. Scott CL, Jenkins MA, Southey MC, et al.: Average age-specific cumulative risk of breast cancer according to type and site of germline mutations in BRCA1 and BRCA2 estimated from multiple-case breast cancer families attending Australian family cancer clinics. Hum Genet 112 (5-6): 542-51, 2003. [PUBMED Abstract]
224. Lubinski J, Phelan CM, Ghadirian P, et al.: Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer 3 (1): 1-10, 2004. [PUBMED Abstract]
225. Satagopan JM, Boyd J, Kauff ND, et al.: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8 (12): 3776-81, 2002. [PUBMED Abstract]
226. Rennert G, Dishon S, Rennert HS, et al.: Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel. Eur J Cancer Prev 14 (4): 357-61, 2005. [PUBMED Abstract]
227. James PA, Sawyer S, Boyle S, et al.: Large genomic rearrangements in the familial breast and ovarian cancer gene BRCA1 are associated with an increased frequency of high risk features. Fam Cancer 14 (2): 287-95, 2015. [PUBMED Abstract]
228. Eisinger F, Jacquemier J, Charpin C, et al.: Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 58 (8): 1588-92, 1998. [PUBMED Abstract]
229. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet 349 (9064): 1505-10, 1997. [PUBMED Abstract]
230. Armes JE, Egan AJ, Southey MC, et al.: The histologic phenotypes of breast carcinoma occurring before age 40 years in women with and without BRCA1 or BRCA2 germline mutations: a population-based study. Cancer 83 (11): 2335-45, 1998. [PUBMED Abstract]
231. Foulkes WD, Stefansson IM, Chappuis PO, et al.: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95 (19): 1482-5, 2003. [PUBMED Abstract]
232. Verhoog LC, Brekelmans CT, Seynaeve C, et al.: Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351 (9099): 316-21, 1998. [PUBMED Abstract]
233. Manié E, Vincent-Salomon A, Lehmann-Che J, et al.: High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res 69 (2): 663-71, 2009. [PUBMED Abstract]
234. Southey MC, Ramus SJ, Dowty JG, et al.: Morphological predictors of BRCA1 germline mutations in young women with breast cancer. Br J Cancer 104 (6): 903-9, 2011. [PUBMED Abstract]
235. Mavaddat N, Barrowdale D, Andrulis IL, et al.: Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21 (1): 134-47, 2012. [PUBMED Abstract]
236. Lakhani SR, Van De Vijver MJ, Jacquemier J, et al.: The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20 (9): 2310-8, 2002. [PUBMED Abstract]
237. Sorlie T, Tibshirani R, Parker J, et al.: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100 (14): 8418-23, 2003. [PUBMED Abstract]
238. Lee E, McKean-Cowdin R, Ma H, et al.: Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol 29 (33): 4373-80, 2011. [PUBMED Abstract]
239. Anders C, Carey LA: Understanding and treating triple-negative breast cancer. Oncology (Williston Park) 22 (11): 1233-9; discussion 1239-40, 1243, 2008. [PUBMED Abstract]
240. Atchley DP, Albarracin CT, Lopez A, et al.: Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26 (26): 4282-8, 2008. [PUBMED Abstract]
241. Tung N, Wang Y, Collins LC, et al.: Estrogen receptor positive breast cancers in BRCA1 mutation carriers: clinical risk factors and pathologic features. Breast Cancer Res 12 (1): R12, 2010. [PUBMED Abstract]
242. Lakhani SR, Khanna KK, Chenevix-Trench G: Are estrogen receptor-positive breast cancers in BRCA1 mutation carriers sporadic? Breast Cancer Res 12 (2): 104, 2010. [PUBMED Abstract]
243. Foulkes WD, Metcalfe K, Sun P, et al.: Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res 10 (6): 2029-34, 2004. [PUBMED Abstract]
244. Gonzalez-Angulo AM, Timms KM, Liu S, et al.: Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17 (5): 1082-9, 2011. [PUBMED Abstract]
245. Rummel S, Varner E, Shriver CD, et al.: Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat 137 (1): 119-25, 2013. [PUBMED Abstract]
246. Couch FJ, Hart SN, Sharma P, et al.: Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33 (4): 304-11, 2015. [PUBMED Abstract]
247. Robertson L, Hanson H, Seal S, et al.: BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer 106 (6): 1234-8, 2012. [PUBMED Abstract]
248. Tun NM, Villani G, Ong K, et al.: Risk of having BRCA1 mutation in high-risk women with triple-negative breast cancer: a meta-analysis. Clin Genet 85 (1): 43-8, 2014. [PUBMED Abstract]
249. Lee LJ, Alexander B, Schnitt SJ, et al.: Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117 (14): 3093-100, 2011. [PUBMED Abstract]
250. Eccles DM, Li N, Handwerker R, et al.: Genetic testing in a cohort of young patients with HER2-amplified breast cancer. Ann Oncol 27 (3): 467-73, 2016. [PUBMED Abstract]
251. Foulkes WD: BRCA1 functions as a breast stem cell regulator. J Med Genet 41 (1): 1-5, 2004. [PUBMED Abstract]
252. Perou CM, Sørlie T, Eisen MB, et al.: Molecular portraits of human breast tumours. Nature 406 (6797): 747-52, 2000. [PUBMED Abstract]
253. Sørlie T, Perou CM, Tibshirani R, et al.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98 (19): 10869-74, 2001. [PUBMED Abstract]
254. Hedenfalk I, Duggan D, Chen Y, et al.: Gene-expression profiles in hereditary breast cancer. N Engl J Med 344 (8): 539-48, 2001. [PUBMED Abstract]
255. Wessels LF, van Welsem T, Hart AA, et al.: Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62 (23): 7110-7, 2002. [PUBMED Abstract]
256. Palacios J, Honrado E, Osorio A, et al.: Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9 (10 Pt 1): 3606-14, 2003. [PUBMED Abstract]
257. Nielsen TO, Hsu FD, Jensen K, et al.: Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10 (16): 5367-74, 2004. [PUBMED Abstract]
258. Palacios J, Honrado E, Osorio A, et al.: Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90 (1): 5-14, 2005. [PUBMED Abstract]
259. Laakso M, Loman N, Borg A, et al.: Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors. Mod Pathol 18 (10): 1321-8, 2005. [PUBMED Abstract]
260. Cheang MC, Voduc D, Bajdik C, et al.: Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14 (5): 1368-76, 2008. [PUBMED Abstract]
261. Hwang ES, McLennan JL, Moore DH, et al.: Ductal carcinoma in situ in BRCA mutation carriers. J Clin Oncol 25 (6): 642-7, 2007. [PUBMED Abstract]
262. Adem C, Reynolds C, Soderberg CL, et al.: Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers. Cancer 97 (1): 1-11, 2003. [PUBMED Abstract]
263. Claus EB, Petruzella S, Matloff E, et al.: Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293 (8): 964-9, 2005. [PUBMED Abstract]
264. Arun B, Vogel KJ, Lopez A, et al.: High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers. Cancer Prev Res (Phila Pa) 2 (2): 122-7, 2009. [PUBMED Abstract]
265. Garber JE: BRCA1/2-associated and sporadic breast cancers: fellow travelers or not? Cancer Prev Res (Phila Pa) 2 (2): 100-3, 2009. [PUBMED Abstract]
266. Smith KL, Adank M, Kauff N, et al.: BRCA mutations in women with ductal carcinoma in situ. Clin Cancer Res 13 (14): 4306-10, 2007. [PUBMED Abstract]
267. Hoogerbrugge N, Bult P, Bonenkamp JJ, et al.: Numerous high-risk epithelial lesions in familial breast cancer. Eur J Cancer 42 (15): 2492-8, 2006. [PUBMED Abstract]
268. Kauff ND, Brogi E, Scheuer L, et al.: Epithelial lesions in prophylactic mastectomy specimens from women with BRCA mutations. Cancer 97 (7): 1601-8, 2003. [PUBMED Abstract]
269. Hall MJ, Reid JE, Wenstrup RJ: Prevalence of BRCA1 and BRCA2 mutations in women with breast carcinoma In Situ and referred for genetic testing. Cancer Prev Res (Phila) 3 (12): 1579-85, 2010. [PUBMED Abstract]
270. Marcus JN, Watson P, Page DL, et al.: Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77 (4): 697-709, 1996. [PUBMED Abstract]
271. Marcus JN, Watson P, Page DL, et al.: BRCA2 hereditary breast cancer pathophenotype. Breast Cancer Res Treat 44 (3): 275-7, 1997. [PUBMED Abstract]
272. Agnarsson BA, Jonasson JG, Björnsdottir IB, et al.: Inherited BRCA2 mutation associated with high grade breast cancer. Breast Cancer Res Treat 47 (2): 121-7, 1998. [PUBMED Abstract]
273. Lakhani SR, Jacquemier J, Sloane JP, et al.: Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 90 (15): 1138-45, 1998. [PUBMED Abstract]
274. Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994. [PUBMED Abstract]
275. Lancaster JM, Wooster R, Mangion J, et al.: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13 (2): 238-40, 1996. [PUBMED Abstract]
276. Miki Y, Katagiri T, Kasumi F, et al.: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13 (2): 245-7, 1996. [PUBMED Abstract]
277. Teng DH, Bogden R, Mitchell J, et al.: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13 (2): 241-4, 1996. [PUBMED Abstract]
278. Berchuck A, Heron KA, Carney ME, et al.: Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 4 (10): 2433-7, 1998. [PUBMED Abstract]
279. Thompson ME, Jensen RA, Obermiller PS, et al.: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 9 (4): 444-50, 1995. [PUBMED Abstract]
280. Dobrovic A, Simpfendorfer D: Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res 57 (16): 3347-50, 1997. [PUBMED Abstract]
281. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al.: Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 8 (4): R38, 2006. [PUBMED Abstract]
282. Turner NC, Reis-Filho JS, Russell AM, et al.: BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26 (14): 2126-32, 2007. [PUBMED Abstract]
283. Rakha EA, El-Sheikh SE, Kandil MA, et al.: Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum Pathol 39 (6): 857-65, 2008. [PUBMED Abstract]
284. Wong EM, Southey MC, Fox SB, et al.: Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila) 4 (1): 23-33, 2011. [PUBMED Abstract]
285. Cleton-Jansen AM, Collins N, Lakhani SR, et al.: Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 72 (5): 1241-4, 1995. [PUBMED Abstract]
286. Hamann U, Herbold C, Costa S, et al.: Allelic imbalance on chromosome 13q: evidence for the involvement of BRCA2 and RB1 in sporadic breast cancer. Cancer Res 56 (9): 1988-90, 1996. [PUBMED Abstract]
287. Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (7035): 917-21, 2005. [PUBMED Abstract]
288. Lakhani SR, Manek S, Penault-Llorca F, et al.: Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin Cancer Res 10 (7): 2473-81, 2004. [PUBMED Abstract]
289. Evans DG, Young K, Bulman M, et al.: Probability of BRCA1/2 mutation varies with ovarian histology: results from screening 442 ovarian cancer families. Clin Genet 73 (4): 338-45, 2008. [PUBMED Abstract]
290. Tonin PN, Maugard CM, Perret C, et al.: A review of histopathological subtypes of ovarian cancer in BRCA-related French Canadian cancer families. Fam Cancer 6 (4): 491-7, 2007. [PUBMED Abstract]
291. Bolton KL, Chenevix-Trench G, Goh C, et al.: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307 (4): 382-90, 2012. [PUBMED Abstract]
292. Liu J, Cristea MC, Frankel P, et al.: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival. Cancer Genet 205 (1-2): 34-41, 2012 Jan-Feb. [PUBMED Abstract]
293. Crum CP, Drapkin R, Kindelberger D, et al.: Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clin Med Res 5 (1): 35-44, 2007. [PUBMED Abstract]
294. Piek JM, van Diest PJ, Zweemer RP, et al.: Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 195 (4): 451-6, 2001. [PUBMED Abstract]
295. Carcangiu ML, Radice P, Manoukian S, et al.: Atypical epithelial proliferation in fallopian tubes in prophylactic salpingo-oophorectomy specimens from BRCA1 and BRCA2 germline mutation carriers. Int J Gynecol Pathol 23 (1): 35-40, 2004. [PUBMED Abstract]
296. Mehra K, Mehrad M, Ning G, et al.: STICS, SCOUTs and p53 signatures; a new language for pelvic serous carcinogenesis. Front Biosci (Elite Ed) 3: 625-34, 2011. [PUBMED Abstract]
297. Powell CB, Chen LM, McLennan J, et al.: Risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers: experience with a consecutive series of 111 patients using a standardized surgical-pathological protocol. Int J Gynecol Cancer 21 (5): 846-51, 2011. [PUBMED Abstract]
298. Finch A, Shaw P, Rosen B, et al.: Clinical and pathologic findings of prophylactic salpingo-oophorectomies in 159 BRCA1 and BRCA2 carriers. Gynecol Oncol 100 (1): 58-64, 2006. [PUBMED Abstract]
299. Medeiros F, Muto MG, Lee Y, et al.: The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol 30 (2): 230-6, 2006. [PUBMED Abstract]
300. Prat J; FIGO Committee on Gynecologic Oncology: Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 124 (1): 1-5, 2014. [PUBMED Abstract]
301. Schorge JO, Muto MG, Lee SJ, et al.: BRCA1-related papillary serous carcinoma of the peritoneum has a unique molecular pathogenesis. Cancer Res 60 (5): 1361-4, 2000. [PUBMED Abstract]
302. Jazaeri AA, Yee CJ, Sotiriou C, et al.: Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst 94 (13): 990-1000, 2002. [PUBMED Abstract]
303. Gourley C, Michie CO, Roxburgh P, et al.: Increased incidence of visceral metastases in scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype. J Clin Oncol 28 (15): 2505-11, 2010. [PUBMED Abstract]
304. Vineyard MA, Daniels MS, Urbauer DL, et al.: Is low-grade serous ovarian cancer part of the tumor spectrum of hereditary breast and ovarian cancer? Gynecol Oncol 120 (2): 229-32, 2011. [PUBMED Abstract]
305. Norquist BM, Harrell MI, Brady MF, et al.: Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2 (4): 482-90, 2016. [PUBMED Abstract]
306. Hilton JL, Geisler JP, Rathe JA, et al.: Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst 94 (18): 1396-406, 2002. [PUBMED Abstract]
307. Quinn JE, James CR, Stewart GE, et al.: BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy. Clin Cancer Res 13 (24): 7413-20, 2007. [PUBMED Abstract]
308. Geisler JP, Hatterman-Zogg MA, Rathe JA, et al.: Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 94 (1): 61-7, 2002. [PUBMED Abstract]
309. Vasen HF: Clinical description of the Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)]. Fam Cancer 4 (3): 219-25, 2005. [PUBMED Abstract]
310. Jascur T, Boland CR: Structure and function of the components of the human DNA mismatch repair system. Int J Cancer 119 (9): 2030-5, 2006. [PUBMED Abstract]
311. Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994. [PUBMED Abstract]
312. Peltomäki P, Vasen HF: Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113 (4): 1146-58, 1997. [PUBMED Abstract]
313. Akiyama Y, Sato H, Yamada T, et al.: Germ-line mutation of the hMSH6/GTBP gene in an atypical hereditary nonpolyposis colorectal cancer kindred. Cancer Res 57 (18): 3920-3, 1997. [PUBMED Abstract]
314. Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997. [PUBMED Abstract]
315. Huang J, Kuismanen SA, Liu T, et al.: MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer. Cancer Res 61 (4): 1619-23, 2001. [PUBMED Abstract]
316. Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994. [PUBMED Abstract]
317. Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al.: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 130 (2): 312-22, 2006. [PUBMED Abstract]
318. Worthley DL, Walsh MD, Barker M, et al.: Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 128 (5): 1431-6, 2005. [PUBMED Abstract]
319. Vasen HF, Mecklin JP, Khan PM, et al.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34 (5): 424-5, 1991. [PUBMED Abstract]
320. Vasen HF, Watson P, Mecklin JP, et al.: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116 (6): 1453-6, 1999. [PUBMED Abstract]
321. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al.: A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89 (23): 1758-62, 1997. [PUBMED Abstract]
322. Umar A, Boland CR, Terdiman JP, et al.: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96 (4): 261-8, 2004. [PUBMED Abstract]
323. Watson P, Lynch HT: Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1 (1): 57-60, 2001. [PUBMED Abstract]
324. Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996. [PUBMED Abstract]
325. Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995. [PUBMED Abstract]
326. Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71 (3): 677-85, 1993. [PUBMED Abstract]
327. Brown GJ, St John DJ, Macrae FA, et al.: Cancer risk in young women at risk of hereditary nonpolyposis colorectal cancer: implications for gynecologic surveillance. Gynecol Oncol 80 (3): 346-9, 2001. [PUBMED Abstract]
328. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999. [PUBMED Abstract]
329. Grindedal EM, Renkonen-Sinisalo L, Vasen H, et al.: Survival in women with MMR mutations and ovarian cancer: a multicentre study in Lynch syndrome kindreds. J Med Genet 47 (2): 99-102, 2010. [PUBMED Abstract]
330. Pal T, Permuth-Wey J, Sellers TA: A review of the clinical relevance of mismatch-repair deficiency in ovarian cancer. Cancer 113 (4): 733-42, 2008. [PUBMED Abstract]
331. Jensen UB, Sunde L, Timshel S, et al.: Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120 (3): 777-82, 2010. [PUBMED Abstract]
332. Shanley S, Fung C, Milliken J, et al.: Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer 8 (3): 251-5, 2009. [PUBMED Abstract]
333. Walsh MD, Buchanan DD, Cummings MC, et al.: Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res 16 (7): 2214-24, 2010. [PUBMED Abstract]
334. Buerki N, Gautier L, Kovac M, et al.: Evidence for breast cancer as an integral part of Lynch syndrome. Genes Chromosomes Cancer 51 (1): 83-91, 2012. [PUBMED Abstract]
335. Win AK, Young JP, Lindor NM, et al.: Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 30 (9): 958-64, 2012. [PUBMED Abstract]
336. Win AK, Lindor NM, Young JP, et al.: Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst 104 (18): 1363-72, 2012. [PUBMED Abstract]
337. Harkness EF, Barrow E, Newton K, et al.: Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J Med Genet 52 (8): 553-6, 2015. [PUBMED Abstract]
338. Win AK, Lindor NM, Jenkins MA: Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res 15 (2): R27, 2013. [PUBMED Abstract]
339. Goldberg M, Bell K, Aronson M, et al.: Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry. J Med Genet 54 (11): 742-746, 2017. [PUBMED Abstract]
340. Roberts ME, Jackson SA, Susswein LR, et al.: MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 20 (10): 1167-1174, 2018. [PUBMED Abstract]
341. Espenschied CR, LaDuca H, Li S, et al.: Multigene Panel Testing Provides a New Perspective on Lynch Syndrome. J Clin Oncol 35 (22): 2568-2575, 2017. [PUBMED Abstract]
342. Lu HM, Li S, Black MH, et al.: Association of Breast and Ovarian Cancers With Predisposition Genes Identified by Large-Scale Sequencing. JAMA Oncol 5 (1): 51-57, 2019. [PUBMED Abstract]
343. Latham A, Srinivasan P, Kemel Y, et al.: Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer. J Clin Oncol 37 (4): 286-295, 2019. [PUBMED Abstract]
344. Harris CC, Hollstein M: Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329 (18): 1318-27, 1993. [PUBMED Abstract]
345. Malkin D: The Li-Fraumeni syndrome. Cancer: Principles and Practice of Oncology Updates 7(7): 1-14, 1993.
346. Gonzalez KD, Noltner KA, Buzin CH, et al.: Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 27 (8): 1250-6, 2009. [PUBMED Abstract]
347. Chompret A, Abel A, Stoppa-Lyonnet D, et al.: Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 38 (1): 43-7, 2001. [PUBMED Abstract]
348. Tinat J, Bougeard G, Baert-Desurmont S, et al.: 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27 (26): e108-9; author reply e110, 2009. [PUBMED Abstract]
349. Bottomley RH, Condit PT: Cancer families. Cancer Bull 20: 22-24, 1968.
350. Bougeard G, Renaux-Petel M, Flaman JM, et al.: Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol 33 (21): 2345-52, 2015. [PUBMED Abstract]
351. Sidransky D, Tokino T, Helzlsouer K, et al.: Inherited p53 gene mutations in breast cancer. Cancer Res 52 (10): 2984-6, 1992. [PUBMED Abstract]
352. Wilson JR, Bateman AC, Hanson H, et al.: A novel HER2-positive breast cancer phenotype arising from germline TP53 mutations. J Med Genet 47 (11): 771-4, 2010. [PUBMED Abstract]
353. Melhem-Bertrandt A, Bojadzieva J, Ready KJ, et al.: Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 118 (4): 908-13, 2012. [PUBMED Abstract]
354. Masciari S, Dillon DA, Rath M, et al.: Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat 133 (3): 1125-30, 2012. [PUBMED Abstract]
355. Pearson AD, Craft AW, Ratcliffe JM, et al.: Two families with the Li-Fraumeni cancer family syndrome. J Med Genet 19 (5): 362-5, 1982. [PUBMED Abstract]
356. Li FP, Fraumeni JF, Mulvihill JJ, et al.: A cancer family syndrome in twenty-four kindreds. Cancer Res 48 (18): 5358-62, 1988. [PUBMED Abstract]
357. Bougeard G, Sesboüé R, Baert-Desurmont S, et al.: Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 45 (8): 535-8, 2008. [PUBMED Abstract]
358. Mai PL, Best AF, Peters JA, et al.: Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 122 (23): 3673-3681, 2016. [PUBMED Abstract]
359. Kamihara J, Rana HQ, Garber JE: Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 35 (6): 654-62, 2014. [PUBMED Abstract]
360. Mai PL, Khincha PP, Loud JT, et al.: Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort. JAMA Oncol 3 (12): 1640-1645, 2017. [PUBMED Abstract]
361. Villani A, Tabori U, Schiffman J, et al.: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12 (6): 559-67, 2011. [PUBMED Abstract]
362. Masciari S, Van den Abbeele AD, Diller LR, et al.: F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA 299 (11): 1315-9, 2008. [PUBMED Abstract]
363. Zhou XP, Waite KA, Pilarski R, et al.: Germline PTEN promoter mutations and deletions in Cowden/Bannayan-Riley-Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73 (2): 404-11, 2003. [PUBMED Abstract]
364. Mester J, Eng C: When overgrowth bumps into cancer: the PTEN-opathies. Am J Med Genet C Semin Med Genet 163C (2): 114-21, 2013. [PUBMED Abstract]
365. Eng C: PTEN: one gene, many syndromes. Hum Mutat 22 (3): 183-98, 2003. [PUBMED Abstract]
366. Marsh DJ, Kum JB, Lunetta KL, et al.: PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 8 (8): 1461-72, 1999. [PUBMED Abstract]
367. Pilarski R, Eng C: Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet 41 (5): 323-6, 2004. [PUBMED Abstract]
368. Eng C: PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, Wash: University of Washington, 1993-2018, pp. Available online. Last accessed June 07, 2019.
369. Pilarski R, Burt R, Kohlman W, et al.: Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst 105 (21): 1607-16, 2013. [PUBMED Abstract]
370. Ngeow J, Liu C, Zhou K, et al.: Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis. J Clin Oncol 33 (23): 2537-44, 2015. [PUBMED Abstract]
371. Tan MH, Mester JL, Ngeow J, et al.: Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res 18 (2): 400-7, 2012. [PUBMED Abstract]
372. Bubien V, Bonnet F, Brouste V, et al.: High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J Med Genet 50 (4): 255-63, 2013. [PUBMED Abstract]
373. Myers MP, Tonks NK: PTEN: sometimes taking it off can be better than putting it on. Am J Hum Genet 61 (6): 1234-8, 1997. [PUBMED Abstract]
374. Hobert JA, Eng C: PTEN hamartoma tumor syndrome: an overview. Genet Med 11 (10): 687-94, 2009. [PUBMED Abstract]
375. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al.: Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer 13 (1): 57-63, 2014. [PUBMED Abstract]
376. Ngeow J, Stanuch K, Mester JL, et al.: Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol 32 (17): 1818-24, 2014. [PUBMED Abstract]
377. Olopade OI, Weber BL: Breast cancer genetics: toward molecular characterization of individuals at increased risk for breast cancer: part I. Cancer: Principles and Practice of Oncology Updates 12 (10): 1-12, 1998.
378. Pilarski R, Stephens JA, Noss R, et al.: Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet 48 (8): 505-12, 2011. [PUBMED Abstract]
379. Nelen MR, Padberg GW, Peeters EA, et al.: Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 13 (1): 114-6, 1996. [PUBMED Abstract]
380. Lachlan KL, Lucassen AM, Bunyan D, et al.: Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet 44 (9): 579-85, 2007. [PUBMED Abstract]
381. Benusiglio PR, Malka D, Rouleau E, et al.: CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study. J Med Genet 50 (7): 486-9, 2013. [PUBMED Abstract]
382. Beeghly-Fadiel A, Lu W, Gao YT, et al.: E-cadherin polymorphisms and breast cancer susceptibility: a report from the Shanghai Breast Cancer Study. Breast Cancer Res Treat 121 (2): 445-52, 2010. [PUBMED Abstract]
383. McVeigh TP, Choi JK, Miller NM, et al.: Lobular breast cancer in a CDH1 splice site mutation carrier: case report and review of the literature. Clin Breast Cancer 14 (2): e47-51, 2014. [PUBMED Abstract]
384. Petridis C, Shinomiya I, Kohut K, et al.: Germline CDH1 mutations in bilateral lobular carcinoma in situ. Br J Cancer 110 (4): 1053-7, 2014. [PUBMED Abstract]
385. Tipirisetti NR, Govatati S, Govatati S, et al.: Association of E-cadherin single-nucleotide polymorphisms with the increased risk of breast cancer: a study in South Indian women. Genet Test Mol Biomarkers 17 (6): 494-500, 2013. [PUBMED Abstract]
386. Fitzgerald RC, Hardwick R, Huntsman D, et al.: Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 47 (7): 436-44, 2010. [PUBMED Abstract]
387. Xie ZM, Li LS, Laquet C, et al.: Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer. Cancer 117 (14): 3112-7, 2011. [PUBMED Abstract]
388. Peutz JL: Very remarkable case of familial polyposis of mucous membrane of intestinal tract and nasopharynx accompanied by peculiar pigmentations of skin and mucous membrane. Ned Tijdschr Geneeskd 10: 134-146, 1921.
389. Jeghers H, McKusick VA, Katz KH: Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med 241 (26): 1031-6, 1949. [PUBMED Abstract]
390. Spigelman AD, Murday V, Phillips RK: Cancer and the Peutz-Jeghers syndrome. Gut 30 (11): 1588-90, 1989. [PUBMED Abstract]
391. Aretz S, Stienen D, Uhlhaas S, et al.: High proportion of large genomic STK11 deletions in Peutz-Jeghers syndrome. Hum Mutat 26 (6): 513-9, 2005. [PUBMED Abstract]
392. Hemminki A, Markie D, Tomlinson I, et al.: A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391 (6663): 184-7, 1998. [PUBMED Abstract]
393. Jenne DE, Reimann H, Nezu J, et al.: Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18 (1): 38-43, 1998. [PUBMED Abstract]
394. Boudeau J, Kieloch A, Alessi DR, et al.: Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients. Hum Mutat 21 (2): 172, 2003. [PUBMED Abstract]
395. Lim W, Hearle N, Shah B, et al.: Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer 89 (2): 308-13, 2003. [PUBMED Abstract]
396. Giardiello FM, Brensinger JD, Tersmette AC, et al.: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119 (6): 1447-53, 2000. [PUBMED Abstract]
397. Hearle N, Schumacher V, Menko FH, et al.: Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 12 (10): 3209-15, 2006. [PUBMED Abstract]
398. Lim W, Olschwang S, Keller JJ, et al.: Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126 (7): 1788-94, 2004. [PUBMED Abstract]
399. van Lier MG, Wagner A, Mathus-Vliegen EM, et al.: High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol 105 (6): 1258-64; author reply 1265, 2010. [PUBMED Abstract]
400. Srivatsa PJ, Keeney GL, Podratz KC: Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz-Jeghers syndrome. Gynecol Oncol 53 (2): 256-64, 1994. [PUBMED Abstract]
401. Scully RE: Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz-Jeghers syndrome. Cancer 25 (5): 1107-21, 1970. [PUBMED Abstract]
402. Westerman AM, Entius MM, de Baar E, et al.: Peutz-Jeghers syndrome: 78-year follow-up of the original family. Lancet 353 (9160): 1211-5, 1999. [PUBMED Abstract]
403. Mehenni H, Resta N, Park JG, et al.: Cancer risks in LKB1 germline mutation carriers. Gut 55 (7): 984-90, 2006. [PUBMED Abstract]
404. Gruber SB, Entius MM, Petersen GM, et al.: Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. Cancer Res 58 (23): 5267-70, 1998. [PUBMED Abstract]
405. Wang ZJ, Ellis I, Zauber P, et al.: Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol 188 (1): 9-13, 1999. [PUBMED Abstract]
406. Miyoshi H, Nakau M, Ishikawa TO, et al.: Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62 (8): 2261-6, 2002. [PUBMED Abstract]
407. Nakau M, Miyoshi H, Seldin MF, et al.: Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62 (16): 4549-53, 2002. [PUBMED Abstract]
408. Takeda H, Miyoshi H, Kojima Y, et al.: Accelerated onsets of gastric hamartomas and hepatic adenomas/carcinomas in Lkb1+/-p53-/- compound mutant mice. Oncogene 25 (12): 1816-20, 2006. [PUBMED Abstract]
409. Amos CI, Keitheri-Cheteri MB, Sabripour M, et al.: Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet 41 (5): 327-33, 2004. [PUBMED Abstract]
410. Reid S, Schindler D, Hanenberg H, et al.: Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39 (2): 162-4, 2007. [PUBMED Abstract]
411. Rahman N, Seal S, Thompson D, et al.: PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39 (2): 165-7, 2007. [PUBMED Abstract]
412. Erkko H, Dowty JG, Nikkilä J, et al.: Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin Cancer Res 14 (14): 4667-71, 2008. [PUBMED Abstract]
413. Heikkinen T, Kärkkäinen H, Aaltonen K, et al.: The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res 15 (9): 3214-22, 2009. [PUBMED Abstract]
414. Ding YC, Steele L, Chu LH, et al.: Germline mutations in PALB2 in African-American breast cancer cases. Breast Cancer Res Treat 126 (1): 227-30, 2011. [PUBMED Abstract]
415. Foulkes WD, Ghadirian P, Akbari MR, et al.: Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res 9 (6): R83, 2007. [PUBMED Abstract]
416. Casadei S, Norquist BM, Walsh T, et al.: Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res 71 (6): 2222-9, 2011. [PUBMED Abstract]
417. Southey MC, Teo ZL, Dowty JG, et al.: A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 12 (6): R109, 2010. [PUBMED Abstract]
418. Hellebrand H, Sutter C, Honisch E, et al.: Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum Mutat 32 (6): E2176-88, 2011. [PUBMED Abstract]
419. Bogdanova N, Sokolenko AP, Iyevleva AG, et al.: PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat 126 (2): 545-50, 2011. [PUBMED Abstract]
420. Wong MW, Nordfors C, Mossman D, et al.: BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127 (3): 853-9, 2011. [PUBMED Abstract]
421. Zheng Y, Zhang J, Niu Q, et al.: Novel germline PALB2 truncating mutations in African American breast cancer patients. Cancer 118 (5): 1362-70, 2012. [PUBMED Abstract]
422. Tischkowitz M, Capanu M, Sabbaghian N, et al.: Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat 33 (4): 674-80, 2012. [PUBMED Abstract]
423. Fernandes PH, Saam J, Peterson J, et al.: Comprehensive sequencing of PALB2 in patients with breast cancer suggests PALB2 mutations explain a subset of hereditary breast cancer. Cancer 120 (7): 963-7, 2014. [PUBMED Abstract]
424. Janatova M, Kleibl Z, Stribrna J, et al.: The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. Cancer Epidemiol Biomarkers Prev 22 (12): 2323-32, 2013. [PUBMED Abstract]
425. Teo ZL, Sawyer SD, James PA, et al.: The incidence of PALB2 c.3113G>A in women with a strong family history of breast and ovarian cancer attending familial cancer centres in Australia. Fam Cancer 12 (4): 587-95, 2013. [PUBMED Abstract]
426. Snyder C, Metcalfe K, Sopik V, et al.: Prevalence of PALB2 mutations in the Creighton University Breast Cancer Family Registry. Breast Cancer Res Treat 150 (3): 637-41, 2015. [PUBMED Abstract]
427. Nguyen-Dumont T, Hammet F, Mahmoodi M, et al.: Mutation screening of PALB2 in clinically ascertained families from the Breast Cancer Family Registry. Breast Cancer Res Treat 149 (2): 547-54, 2015. [PUBMED Abstract]
428. Damiola F, Schultz I, Barjhoux L, et al.: Mutation analysis of PALB2 gene in French breast cancer families. Breast Cancer Res Treat 154 (3): 463-71, 2015. [PUBMED Abstract]
429. Antoniou AC, Casadei S, Heikkinen T, et al.: Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371 (6): 497-506, 2014. [PUBMED Abstract]
430. Cybulski C, Kluźniak W, Huzarski T, et al.: Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 16 (6): 638-44, 2015. [PUBMED Abstract]
431. Jones S, Hruban RH, Kamiyama M, et al.: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324 (5924): 217, 2009. [PUBMED Abstract]
432. Slater EP, Langer P, Niemczyk E, et al.: PALB2 mutations in European familial pancreatic cancer families. Clin Genet 78 (5): 490-4, 2010. [PUBMED Abstract]
433. Hofstatter EW, Domchek SM, Miron A, et al.: PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer 10 (2): 225-31, 2011. [PUBMED Abstract]
434. Stadler ZK, Salo-Mullen E, Sabbaghian N, et al.: Germline PALB2 mutation analysis in breast-pancreas cancer families. J Med Genet 48 (8): 523-5, 2011. [PUBMED Abstract]
435. Ghiorzo P, Pensotti V, Fornarini G, et al.: Contribution of germline mutations in the BRCA and PALB2 genes to pancreatic cancer in Italy. Fam Cancer 11 (1): 41-7, 2012. [PUBMED Abstract]
436. Westerman AM, Entius MM, Boor PP, et al.: Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families. Hum Mutat 13 (6): 476-81, 1999. [PUBMED Abstract]
437. Schreibman IR, Baker M, Amos C, et al.: The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 100 (2): 476-90, 2005. [PUBMED Abstract]
438. Gonzalez KD, Buzin CH, Noltner KA, et al.: High frequency of de novo mutations in Li-Fraumeni syndrome. J Med Genet 46 (10): 689-93, 2009. [PUBMED Abstract]
439. Bendig I, Mohr N, Kramer F, et al.: Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet 154 (1): 22-6, 2004. [PUBMED Abstract]
440. De Leeneer K, Coene I, Crombez B, et al.: Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing. Breast Cancer Res Treat 132 (1): 87-95, 2012. [PUBMED Abstract]
441. Diez O, Gutiérrez-Enríquez S, Mediano C, et al.: A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 121 (1): 221-5, 2010. [PUBMED Abstract]
442. Garcia-Casado Z, Romero I, Fernandez-Serra A, et al.: A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 12: 134, 2011. [PUBMED Abstract]
443. Hansen TV, Bisgaard ML, Jønson L, et al.: Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 9: 58, 2008. [PUBMED Abstract]
444. Kwong A, Ng EK, Tang EY, et al.: A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer. Fam Cancer 10 (2): 233-7, 2011. [PUBMED Abstract]
445. Marshall M, Solomon S, Lawrence Wickerham D: Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet 76 (5): 427-30, 2009. [PUBMED Abstract]
446. Robson M, Scheuer L, Nafa K, et al.: Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet 39 (2): 126-8, 2002. [PUBMED Abstract]
447. Tesoriero A, Andersen C, Southey M, et al.: De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65 (2): 567-9, 1999. [PUBMED Abstract]
448. van der Luijt RB, van Zon PH, Jansen RP, et al.: De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet 38 (2): 102-5, 2001. [PUBMED Abstract]
449. Morak M, Laner A, Scholz M, et al.: Report on de-novo mutation in the MSH2 gene as a rare event in hereditary nonpolyposis colorectal cancer. Eur J Gastroenterol Hepatol 20 (11): 1101-5, 2008. [PUBMED Abstract]
450. Plasilova M, Zhang J, Okhowat R, et al.: A de novo MLH1 germ line mutation in a 31-year-old colorectal cancer patient. Genes Chromosomes Cancer 45 (12): 1106-10, 2006. [PUBMED Abstract]
451. Win AK, Jenkins MA, Buchanan DD, et al.: Determining the frequency of de novo germline mutations in DNA mismatch repair genes. J Med Genet 48 (8): 530-4, 2011. [PUBMED Abstract]
452. Anderson KG: How well does paternity confidence match actual paternity? Evidence from worldwide nonpaternity rates. Curr Anthropol 47 (3): 513-20, 2006. Also available onlineExit Disclaimer. Last accessed June 07, 2019.
453. Sasse G, Müller H, Chakraborty R, et al.: Estimating the frequency of nonpaternity in Switzerland. Hum Hered 44 (6): 337-43, 1994 Nov-Dec. [PUBMED Abstract]
454. Voracek M, Haubner T, Fisher ML: Recent decline in nonpaternity rates: a cross-temporal meta-analysis. Psychol Rep 103 (3): 799-811, 2008. [PUBMED Abstract]