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

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

Moderate-Penetrance Genes Associated With Breast and/or Gynecologic Cancer

Background

Pathogenic variants in BRCA1, BRCA2, PALB2, and the genes involved in other rare syndromes discussed in the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section of this summary account for less than 25% of the familial risk of breast cancer.[1] Despite intensive genetic linkage studies, there do not appear to be other high-penetrance genes that account for a significant fraction of the remaining multiple-case familial clusters.[2] However, several moderate-penetrance genes associated with breast and/or gynecologic cancers have been identified. Genes such as CHEK2 and ATM are associated with a 20% or higher lifetime risk of breast cancer;[3,4] similarly, genes such as RAD51C, RAD51D, and BRIP1 are associated with a 5% to 10% risk of ovarian cancer.[5,6] Many of these genes are now included on multigene panels, although the clinical actionability of these findings remains uncertain and under investigation.

Breast and Gynecologic Cancer Susceptibility Genes Identified Through Candidate Gene Approaches

There is a very large literature of genetic epidemiology studies describing associations between various loci and breast cancer risk. Many of these studies suffer from significant design limitations. Perhaps as a consequence, most reported associations do not replicate in follow-up studies. This section is not a comprehensive review of all reported associations. This section describes associations that are believed by the editors to be clinically valid, in that they have been described in several studies or are supported by robust meta-analyses. The clinical utility of these observations remains unclear, however, as the risks associated with these variations usually fall below a threshold that would justify a clinical response.

Fanconi anemia genes

Fanconi anemia (FA) is a rare, inherited condition characterized by bone marrow failure, increased risk of malignancy, and physical abnormalities. To date, 16 FA-related genes, including BRCA1 and BRCA2, have been identified (as outlined in Table 10). FA is mainly an autosomal recessive condition, except when caused by pathogenic variants in FANCB, which is X-linked recessive. FANCA accounts for 60% to 70% of pathogenic variants, FANCC accounts for approximately 14%, and the remaining genes each account for 3% or fewer.[7]

Table 10. Fanconi Anemia Genes and Breast Cancer Risk

High-Risk Genes

– BRCA1 (FANCS)a

– BRCA2 (FANCD1)a

– PALB2 (FANCN)b

Moderate-Risk Genesc

– BRIP1 (FANCJ/BACH1)

– FANCD2

– RAD51C (FANCO)

Genes With Uncertain or No Significantly Increased Risk

– FANCA

– FANCB

– FANCC

– FANCE

– FANCF

– FANCG (XRCC9)

– FANCI (KIAA1794)

– FANCL

– SLX4 (FANCP)

– ERCC4 (FANCQ/XPF)

Progressive bone marrow failure typically occurs in the first decade, with patients often presenting with thrombocytopenia or leucopenia. The incidence of bone marrow failure is 90% by age 40 to 50 years. The incidence is 10% to 30% for hematologic malignancies (primarily acute myeloid leukemia) and 25% to 30% for nonhematologic malignancies (solid tumors, particularly of the head and neck, skin, gastrointestinal [GI] tract, and genital tract). Physical abnormalities, including short stature, abnormal skin pigmentation, radial ray defects (including malformation of the thumbs), abnormalities of the urinary tract, eyes, ears, heart, GI system, and central nervous system, hypogonadism, and developmental delay are present in 60% to 75% of affected individuals.[7]

Variants in some of the FA genes, most notably BRCA1 and BRCA2, but also PALB2, RAD51C (in the RAD51 family of genes), and BRIP1, among others, may predispose to breast cancer in heterozygotes. Given the widespread availability of multigene (panel) tests, genetic testing of many of the FA genes is frequently performed despite uncertain cancer risks and the lack of available evidence-based medical management recommendations for many of these genes.

FA gene pathogenic variant carrier status can have implications for reproductive decision making because pathogenic variants in these genes can lead to serious childhood onset of disease if both parents are carriers of pathogenic variants in the same gene. Partner testing may be considered.

BRIP1

BRIP1 (also known as BACH1) encodes a helicase that interacts with the BRCA1 C-terminal (BRCT) domain. This gene also has a role in BRCA1-dependent DNA repair and cell cycle checkpoint function. Biallelic pathogenic variants in BRIP1 are a cause of FA,[8-10] much like such pathogenic variants in BRCA2. Inactivating variants of BRIP1 are associated with an increased risk of breast cancer. In one study, more than 3,000 individuals from BRCA1/BRCA2 pathogenic variant–negative families were examined for BRIP1 variants. Pathogenic variants were identified in 9 of 1,212 individuals with breast cancer but in only 2 of 2,081 controls (P = .003). The relative risk (RR) of breast cancer was estimated to be 2.0 (95% confidence interval [CI], 1.2–3.2; P = .012). Of note, in families with BRIP1 pathogenic variants and multiple cases of breast cancer, there was incomplete segregation of the pathogenic variant with breast cancer, consistent with a low-penetrance allele and similar to that seen with CHEK2.[11] In a case-control study of 3,236 women with ovarian cancer, BRIP1 pathogenic variants were more frequently associated with ovarian cancer risk (RR, 11.2; 95% CI, 3.2–34.1).[12]

CHEK2

CHEK2 is a gene involved in the DNA damage repair response pathway. Based on numerous studies, a polymorphism, 1100delC, appears to be a rare, moderate-penetrance cancer susceptibility allele.[13-18] One study identified the pathogenic variant in 1.2% of the European controls, 4.2% of the European BRCA1/BRCA2-negative familial breast cancer cases, and 1.4% of unselected female breast cancer cases.[13] In a group of 1,479 Dutch women younger than 50 years with invasive breast cancer, 3.7% were found to have the CHEK2 1100delC pathogenic variant.[19] In additional European and U.S. (where the pathogenic variant appears to be slightly less common) studies, including a large prospective study,[20] the frequency of CHEK2 pathogenic variants detected in familial breast or ovarian cancer cases has ranged from 0% [21] to 11%; overall, these studies have found an approximately 1.5-fold to 3-fold increased risk of female breast cancer.[20,22-25] A multicenter combined analysis and reanalysis of nearly 20,000 subjects from ten case-control studies, however, has verified a significant 2.3-fold excess of breast cancer among carriers of pathogenic variants.[26] A subsequent meta-analysis based on 29,154 cases and 37,064 controls from 25 case-control studies found a significant association between CHEK2 1100delC heterozygotes and breast cancer risk (odds ratio [OR], 2.75; 95% CI, 2.25–3.36). The ORs and CIs in unselected, familial, and early-onset breast cancer subgroups were 2.33 (1.79–3.05), 3.72 (2.61–5.31), and 2.78 (2.28–3.39), respectively. However, study limitations included pooling of populations without subgroup analysis, using a mix of population-based and hospital-based controls, and basing results on unadjusted estimates (as cases and controls were matched on only a few common factors); therefore, results should be interpreted in the context of these limitations.[27] In a series of male breast cancer patients, the CHEK2 1100delC variant was significantly more frequently identified than in controls, suggesting that this variant is also associated with an increased risk of male breast cancer.[28]

Two studies have suggested that the risk associated with a CHEK2 1100delC pathogenic variant was stronger in the families of probands ascertained because of bilateral breast cancer.[29,30] Furthermore, a meta-analysis of carriers of 1100delC pathogenic variants estimated the risk of breast cancer to be 42% by age 70 years in women with a family history of breast cancer.[31] Similarly, a Polish study reported that CHEK2 truncating pathogenic variants confer breast cancer risks based on a family history of breast cancer as follows: no family history: 20%; one second-degree relative: 28%; one first-degree relative: 34%; and both first- and second-degree relatives: 44%.[3] Moreover, a Dutch study suggested that female homozygotes for the CHEK2 1100delC variant have a greater-than-twofold increased breast cancer risk compared with heterozygotes.[32] Although there have been conflicting reports regarding cancers other than breast cancer associated with CHEK2 pathogenic variants, this may be dependent on variant type (i.e., missense vs. truncating) or population studied and is not currently of clinical utility.[18,23,33-38] The contribution of CHEK2 variants to breast cancer may depend on the population studied, with a potentially higher variant prevalence in Poland.[39] Carriers of CHEK2 variants in Poland may be more susceptible to estrogen receptor (ER)–positive breast cancer.[40]

Currently, the clinical applicability of CHEK variants remains uncertain because of low variant prevalence and lack of guidelines for clinical management.[41]

A large Dutch study of 86,975 individuals reported an increased risk of cancers other than breast and colon for carriers of the CHEK2 1100delC pathogenic variant,[42] although additional studies are needed to further refine these risks.

(Refer to the CHEK2 section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

ATM

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurologic deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygote carriers of ATM variants.[43] More than 300 variants in the gene have been identified, most of which are truncating variants.[44] ATM proteins have been shown to play a role in cell cycle control.[45-47] In vitro, AT-deficient cells are sensitive to ionizing radiation and radiomimetic drugs, and lack cell cycle regulatory properties after exposure to radiation.[48] There is insufficient evidence to recommend against radiation therapy in carriers of a single ATM pathogenic variant (heterozygotes).

Initial studies searching for an excess of ATM pathogenic variants among breast cancer patients provided conflicting results, perhaps due to study design and variant testing strategies.[49-59] However, two large epidemiologic studies have demonstrated a statistically increased risk of breast cancer among female heterozygote carriers, with an estimated RR of approximately 2.0.[4,59] A meta-analysis modeled the risk of breast cancer to be 6.02% by age 50 years and 32.83% by age 80 years.[60] Given these risks, increased screening and other recommendations based on family history and age may be considered.

Some studies have shown an association between ATM and ovarian cancer,[61,62] although, at this time, there is no evidence to suggest an impact on risk management or disease characteristics.

CASP8 and TGFB1

The Breast Cancer Association Consortium (BCAC), an international group of investigators, investigated single nucleotide polymorphisms (SNPs) identified in previous studies as possibly associated with excess breast cancer risk in 15,000 to 20,000 cases and 15,000 to 20,000 controls. Two SNPs, CASP8 D302H and TGFB1 L10P, were associated with invasive breast cancer with RRs of 0.88 (95% CI, 0.84–0.92) and 1.08 (95% CI, 1.04–1.11), respectively.[63]

RAD51

RAD51 and the family of RAD51-related genes, also known as RAD51 paralogs, are thought to encode proteins that are involved in DNA damage repair through homologous recombination and interaction with numerous other DNA repair proteins, including BRCA1 and BRCA2. RAD51 protein plays a central role in single-strand annealing in the DNA damage response. RAD51 recruitment to break sites and recombinational DNA repair depend on the RAD51 paralogs, although their precise cellular functions are poorly characterized.[64] Variants in these genes are thought to result in loss of RAD51 focus formation in response to DNA damage.[65]

One of five RAD51-related genes, RAD51C has been reported to be linked to both FA-like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. In a study of 480 German families characterized by breast and ovarian cancers who were negative for BRCA1 and BRCA2 pathogenic variants, six monoallelic variants in RAD51C were found (frequency of 1.3%).[66] Another study screened 286 BRCA1/BRCA2-negative patients with breast cancer and/or ovarian cancer and found one likely pathogenic variant in RAD51C-G153D.[67] RAD51C pathogenic variants have also been reported in Australian, British, Finnish, and Spanish non-BRCA1/BRCA2 ovarian cancer–only and breast/ovarian cancer families, and in unselected ovarian cancer cases, with frequencies ranging from 0% to 3% in these populations.[5,12,68-73] In a sample of 206 high-risk Jewish women (including 79 of Ashkenazi origin) previously tested for the common Jewish pathogenic variants, two previously described and possibly pathogenic missense variants were detected.[74] Four additional studies were unable to confirm an association between the RAD51C gene and hereditary breast cancer or ovarian cancer.[75-78]

In addition to carriers of RAD51C pathogenic variants, there are other RAD51 paralogs, including RAD51B, RAD51D, RAD51L1, XRCC2, and XRCC3, that may be associated with breast and/or ovarian cancer risk,[6,12,79-83] although the clinical significance of these findings is unknown. In a case-control study of 3,429 ovarian cancer patients, RAD51C and RAD51D pathogenic variants were more commonly found in ovarian cancer cases (0.82%) than in controls (0.11%, P < .001).[84]

In addition to germline variants, different polymorphisms of RAD51 have been hypothesized to have reduced capacity to repair DNA defects, resulting in increased susceptibility to familial breast cancer. The Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) pooled data from 8,512 carriers of BRCA1 and BRCA2 pathogenic variants and found evidence of an increased risk of breast cancer among women who were BRCA2 carriers and who were homozygous for CC at the RAD51 135G→C SNP (hazard ratio, 1.17; 95% CI, 0.91–1.51).[85]

Several meta-analyses have investigated the association between the RAD51 135G→C polymorphism and breast cancer risk. There is significant overlap in the studies reported in these meta-analyses, significant variability in the characteristics of the populations included, and significant methodologic limitations to their findings.[86-89] A meta-analysis of nine epidemiologic studies involving 13,241 cases and 13,203 controls of unknown BRCA1/BRCA2 status found that women carrying the CC genotype had an increased risk of breast cancer compared with women with the GG or GC genotype (OR, 1.35; 95% CI, 1.04–1.74). A meta-analysis of 14 case-control studies involving 12,183 cases and 10,183 controls confirmed an increased risk only for women who were known BRCA2 carriers (OR, 4.92; 95% CI, 1.10–21.83).[90] Another meta-analysis of 12 studies included only studies of known BRCA-negative cases and found no association between RAD51 135G→C and breast cancer.[91]

In summary, among this conflicting data is substantial evidence for a modest association between germline variants in RAD51C and breast cancer and ovarian cancer. There is also evidence of an association between polymorphisms in RAD51 135G→C among women with homozygous CC genotypes and breast cancer, particularly among BRCA2 carriers. These associations are plausible given the known role of RAD51 in the maintenance of genomic stability.

Abraxas

Pathogenic variants in the BRCA1-interacting gene Abraxas were found in three Finnish breast cancer families and no controls.[92] The significance of this finding outside of this population is not yet known.

RECQL

Through full exome sequencing among high-risk Polish and Quebec-based French Canadian families, the RECQL gene was discovered to harbor multiple rare truncating variants in both populations.[93] (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for more information about whole-exome sequencing.) In the same populations, truncating variants in this gene were also identified in two subsequent validation phases among additional breast cancer patients from high-risk families, and among additional breast cancer cases in which the variant frequency was higher than that observed among controls. A case-control study from Belarus and Germany looked at the most common pathogenic variant, c.1667_1667+3delA GTA, and found it to be linked to ER-positive breast cancer. The OR in this study alone was 1.23 (95% CI, 0.44–3.47; P = .69), but in a meta-analysis with a Polish study, the OR was 2.51 (95% CI, 1.13–5.57, P = .02).[94] Although study results suggest that truncating germline RECQL pathogenic variants are associated with an increased risk of breast cancer, the exact magnitude of risk remains uncertain, and future studies are needed to determine clinical usefulness. Furthermore, the significance of this finding outside of these two populations is not yet known.

SMARCA4

SMARCA4 encodes BRG1 and is a catalytic subunit of the SWI/SNF chromatin remodeling complex, which plays a major role in rendering chromatin accessible to regulation of gene expression.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that has an early age at onset (before age 40 y) and a poor prognosis.[95-97] Familial clustering is sometimes present. SCCOHT tumors may be unilateral or bilateral and have been characterized histologically by the presence of small hyperchromatic cells with brisk mitotic activity.[96] A multimodality approach including surgery, chemotherapy, and radiation therapy has been suggested for the treatment of SCCOHT.[96,97] Given the paraneoplastic phenomenon of hypercalcemia in 60% of cases, tracking calcium levels is useful in monitoring the course of disease. With a wide range of differential diagnoses including germ cell tumors, sex cord–stromal tumors, and undifferentiated carcinomas, SCCOHT remains classified by the World Health Organization as a "miscellaneous tumor" but more recently has been sequenced to be a malignant rhabdoid tumor.[98] Through exome sequencing, most cases of SCCOHT have been found to lack functional SMARCA4/BRG1; in fact, pathogenic variants in SMARCA4 may be the sole variants responsible for SCCOHT.

Despite only approximately 300 cases in the literature, three separate research groups showed SCCOHT to be associated with germline pathogenic variants and somatic mutations in the SMARCA4 gene. In one study of 12 young women with SCCOHT, sequencing of paired tumor and normal samples identified inactivating biallelic SMARCA4 pathogenic variants in each case.[99] Only four additional nonrecurrent somatic genes were identified in any of the other 278 genes sequenced. Immunohistochemistry demonstrated loss of SMARCA4 protein expression in seven of nine tested cases, consistent with a tumor-suppressor gene function. In a second study of another 12 patients, next-generation sequencing also identified SMARCA4 as the only recurrently variant gene, with the majority of variants predicted to result in a truncated protein.[100] A third study included three families in whom whole-exome sequencing with Sanger sequencing confirmation identified at least one germline pathogenic variant or somatic mutation in 24 of 26 cases.[101] Overall, 38 of 43 (88%) of SCCOHT tumors showed loss of SMARCA4 expression, in comparison to only 1 of 139 (0.7%) other ovarian tumor types.

Because of the rarity of this tumor, the penetrance of SMARCA4 is unknown. There is currently no consensus for management, yet SMARCA4 is on the larger multigene panels currently available for genetic testing, and risk-reducing surgery has been offered to pathogenic variant carriers.[102]

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