lunes, 1 de agosto de 2016

Genetics of Colorectal Cancer (PDQ®)—Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)–Health Professional Version



SECTIONS



Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women.
Estimated new cases and deaths from CRC in 2016:[1]
  • New cases: 134,490.
  • Deaths: 49,190.
About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 25% of patients have a family history of CRC that suggests a hereditary contribution, common exposures among family members, or a combination of both. Genetic mutations have been identified as the cause of inherited cancer risk in some colon cancer–prone families; these mutations are estimated to account for only 5% to 6% of CRC cases overall. It is likely that other undiscovered genes and background genetic factors contribute to the development of familial CRC in conjunction with nongenetic risk factors.
(Refer to the PDQ summaries on Colorectal Cancer Screening; Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment for more information about sporadic CRC.)

Natural History of CRC

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).
Pathologists have classified the lesions into the following three groups:
  1. Nonneoplastic polyps (hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid polyps), which have not generally been thought of as precursors of cancer.
  2. Neoplastic polyps (adenomatous polyps and adenomas).
  3. Cancers.
Research, however, does suggest a substantial risk of colon cancer in individuals with juvenile polyposis syndrome and Peutz-Jeghers syndrome, although the nonadenomatous polyps associated with these syndromes have historically been viewed as nonneoplastic.[2-4]
Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[5]
Two complementary interpretations of this observation are as follows:
  1. The adenoma may reflect an innate or acquired tendency of the colon to form tumors.
  2. Adenomas are the primary precursor lesion of colon cancer.
More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,[6-10] based upon the following important observations:
  1. Benign and malignant tissue occur within colorectal tumors.[11]
  2. When patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.[12]
The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[11]
  1. Larger size.
  2. Villous pathology.
  3. The degree of dysplasia within the adenoma.
In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[13,14] While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat, and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven.[15,16] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[17]

Molecular Events Associated With Colon Carcinogenesis

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[18-20] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[21,22] At least five to seven major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonalfashion to carcinoma. There are at least two major pathways by which these molecular events can lead to CRC. While the majority of CRCs are due to events that result inchromosomal instability (CIN), 20% to 30% of CRCs display characteristic patterns of gene hypermethylation, termed CpG island methylator phenotype (CIMP), of which a portion display microsatellite instability (15% of CRCs).[20,23-27]
The spectrum of somatic mutations contributing to the pathogenesis of CRC is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of CRCs found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of CRC, and individual CRCs harbored an average of nine mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature.[28]
Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and frequent detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRASoncogene. The important genes involved in these chromosome losses are APC (5q),DCC/MADH2/MADH4 (18q), and TP53 (17p),[19,29] and chromosome losses are associated with instability at the molecular and chromosomal level.[20] Among the earliest events in the colorectal tumor progression pathway is loss of the APC gene, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors. Acquired or inherited mutations of DNA damage-repair genes also play a role in predisposing colorectal epithelial cells to mutations. Furthermore, the specific genes that undergo somatic mutations and the specific type of mutations the tumor acquires may influence the rate of tumor growth or type of pathologic change in the tumors.[29] For example, the rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors compared with microsatellite-stable tumors. Characteristic histologic changes such as increased mucin production can be seen in tumors that demonstrate microsatellite instability (MSI), suggesting that at least some molecular events contribute to the histologic features of the tumors.
The key characteristics of MSI cancers are that they are tumors with a largely intact chromosome complement and that, as a result of defects in the DNA mismatch repair (MMR) system, they more readily acquire mutations in important cancer-associated genes compared with cells that have an effective DNA MMR system. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.
The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APCgene product, which appears to be consistent with its important role in predisposing persons with germline APC mutations to colorectal tumors.

Family History as a Risk Factor for CRC

Some of the earliest studies of family history of CRC were those of Utah families that reported a higher number of deaths from CRC (3.9%) among the first-degree relatives of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[30] This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[31-36]
Population-based studies have shown a familial association for close relatives of colon cancer patients to develop CRC and other cancers.[37] Using data from a cancer family clinic patient population, the relative and absolute risk of CRC for different family history categories was estimated (see Table 1).[38,39]
A systematic review and meta-analysis of familial CRC risk was reported.[39] Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected first-degree relative. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected first-degree family member. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed a RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).
The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one first-degree relative with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years, for family members of index cases diagnosed at ages 45 to 59 years, and for family members of index cases diagnosed at age 60 years or older, respectively (RR, 3.87; 95% CI, 2.40–6.22 vs. RR, 2.25; 95% CI, 1.85–2.72 vs. RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in a first-degree relative was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had a first-degree relative with an adenoma.[39] This finding has been corroborated.[40] Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR.[41,42] As with any meta-analysis, there could be potential biases that might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included; publication bias; and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.
Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)
Family HistoryRelative Risk of CRC [39]Absolute Risk (%) of CRC by Age 79 ya
CI = confidence interval.
aData from the Surveillance, Epidemiology, and End Results database.
bThe absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC [39] and the absolute risk of CRC by age 79 yearsa.
No family history14a
One first-degree relative with CRC2.3 (95% CI, 2.0–2.5)9b
More than one first-degree relative with CRC4.3 (95% CI, 3.0–6.1)16b
One affected first-degree relative diagnosed with CRC before age 45 y3.9 (95% CI, 2.4–6.2)15b
One first-degree relative with colorectal adenoma2.0 (95% CI, 1.6–2.6)8b
When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Young subjects who report a positive family history of CRC are more likely to represent a high-risk pedigree than older individuals who report a positive family history.[43] Computer models are now available to estimate the probability of developing CRC. These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. At least three validated models are also available for predicting the probability of carrying a mutation in a MMR gene.[44-46]
Figure 1 shows the types of colon cancer cases that arise in various family risk settings.[47]
ENLARGEPie chart showing the fractions of colon cancer cases that arise in various family risk settings. The majority of colon cancer cases diagnosed in these settings are sporadic. The remaining cancer cases are: cases with familial risk (10%–30%); Lynch syndrome (hereditary nonpolyposis colorectal cancer) (2%–3%); familial adenomatous polyposis (<1%); and hamartomatous polyposis syndrome (<0.1%).
Figure 1. The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000), with permission from Elsevier.

Inheritance of CRC Predisposition

Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all gene mutations known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[48] To date, at least one example of autosomal recessive inheritance, MYH-associated polyposis (MAP), has been identified. (Refer to the MYH-Associated Polyposis [MAP] section of this summary for more information.) Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing mutation. These include the following:
  1. Vertical transmission of cancer predisposition in autosomal dominant conditions. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)
  2. Inheritance risk of 50% for both males and females. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. The risk is the same for both male and female children.
  3. Other clinical characteristics also suggest inherited risk:
    • Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic (nongenetic) cases.[49]
    • A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
    • In addition, two or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., two separate primary CRCs) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).
    • The presence of non-neoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoids in familial adenomatous polyposis [FAP]).
    • An uncommon tumor (e.g., adrenocortical, sebaceous carcinoma, ampullary, and small bowel) may serve as a clue to the presence of a hereditary cancer syndrome, such as Li-Fraumeni or FAP.
    • The presence of multiple polyps may suggest a hereditary colon cancer predisposition syndrome. As susceptibility to oligopolyposis (as few as 10–15 polyps) has become apparent, clinicians, and GI endoscopists in particular, increasingly consider the possibility of inherited conditions, such as AFAP, MYH-associated polyposis, and POLD1/POLE, even when the family history appears entirely negative. Because oligopolyposis also involves diverse pathology (including hamartomas, sessile serrated polyps, and sessile serrated adenomas), careful attention to polyp count and polyp histologies helps to determine whether genetic testing and/or further clinical evaluation is appropriate.
Hereditary CRC has two well-described forms: FAP (including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene,[50-57] and Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline mutations in DNA MMR genes.[58-61] (Figure 2 depicts a classic family with LS, highlighting some of the indicators of high CRC risk that are described above.) Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC.[48]
ENLARGEPedigree showing some of the classic features of a family with Lynch syndrome across three generations, including transmission occurring through maternal and paternal lineages and the presence of both colon and endometrial cancers.
Figure 2. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.

Difficulties in Identifying a Family History of CRC Risk

The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[62] In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incompletepenetrance, some persons may carry a genetic predisposition to CRC but do not develop cancer, giving the impression of skipped generations in a family tree.
Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of LS. (Refer to the Accuracy of the Family History section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Several approaches are available to evaluate a patient with newly diagnosed CRC who may or may not be suspected of having a cancer genetics syndrome. The clinician may suspect a potential inherited disposition based on the family history and physical exam, and genetic tests are available to confirm these suspicions. The American College of Medical Genetics and Genomics has published guidelines for evaluating patients with suspected colon cancer susceptibility syndromes.[63] The guidelines aim to identify individuals whose clinical features warrant referral for genetics consultation. If an individual has multiple polyps (>20), depending on the histology, specific gene-directed testing can be a useful diagnostic tool. Similarly, if a patient’s clinical presentation is suspicious for LS, germline genetic testing can be directed towards this syndrome. However, diagnosis is more challenging when the clinical picture is less clear. Currently, tumor screening for LS is the most commonly accepted approach. However, increasingly, panels characterizing somatic mutations in tumors are being utilized for a variety of clinical decisions.
A priori risk-assessment testing (which models risk based on a variety of factors, such as age at cancer onset and the spectrum of tumors in the family) may be an appropriate alternative in many cases. Application of such risk models does anticipate the use ofmultigene (panel) testing, the exact role for which remains to be established.

Other Risk Factors for CRC

Other risk factors that may influence the development of adenomatous polyps and CRC risk include diet, use of nonsteroidal anti-inflammatory drugs (NSAIDs), cigarette smoking, colonoscopy with removal of adenomatous polyps, and physical activity. Even in LS, a hereditary form of colon cancer, cigarette smoking has been identified as a risk factor for the development of colorectal adenomas.[64] (Refer to the Lynch Syndrome [LS] section of this summary for more information).
(Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.)

Interventions

In practical terms, knowing that a person is at an increased risk of CRC because of a germline abnormality is most useful if the knowledge can be used to prevent the development of cancer or cancer-related morbidity and mortality once it has developed. While one can also use the information for family planning, decisions about work and retirement, and other important life decisions, prevention is usually the central concern.
This section covers screening: testing in the absence of symptoms for CRC and its precursors (i.e., adenomatous polyps) to identify people with an increased probability of developing CRC. Those with abnormalities should undergo diagnostic testing to see whether they have an occult cancer, followed by treatment if cancer or a precursor is found. Taken together, this set of activities is aimed at either preventing the development of CRC by finding and removing its precursor, the adenomatous polyp, or increasing the likelihood of cure by early detection and treatment.
In the context of high-risk syndromes such as LS or FAP, surveillance implies examining patients in whom adenoma or cancer occurrence is highly probable, and the examination is done for early detection. It is not screening in the traditional sense. The meaning of the terms screening versus surveillance has evolved over time and their usage in this summary may not be consistent with other oncologic and epidemiologic contexts.
Primary prevention (eliminating the causes of CRC in people with genetically increased risk) is addressed later in this section.

State of the evidence base

Currently, there are no published randomized controlled trials of surveillance in people with a genetically increased risk of CRC and few controlled comparisons. While a randomized trial with a no-surveillance arm is not feasible, there is a need for well-designed studies comparing various surveillance methods or differing periods of time between procedures. An observational study that compared surveilled subjects with unsurveilled (by choice) controls evaluated a 15-year experience with 252 relatives at risk of LS, 119 of whom declined surveillance. Eight of 133 (6%) in the surveilled group developed CRC, compared with 19 in the unsurveilled group (16%, P = .014).[65] In general, however, people with genetic risk have been excluded from the trials of CRC screening that have been published thus far, so it is not possible to estimate effectiveness by subgroup analyses. Therefore, prevention in these patients cannot be based on strong evidence of effectiveness, as is ordinarily relied on by expert groups when suggesting screening or surveillance guidelines.
Given these considerations, clinical decisions are based on clinical judgment. These decisions take into account the biologic and clinical behavior of each kind of genetic condition, and possible parallels with patients at average risk, for whom screening is known to be effective.
The evidence base for the effectiveness of screening in average-risk people (those without apparent genetic risk) is the benchmark for considering an approach to people at increased risk. (Refer to the PDQ summary on Screening for Colorectal Cancer for more information.)
The fact that screening of average-risk persons reduces the risk of dying from CRC forms the basis for recommending surveillance in persons at a higher genetic risk of CRC. As logical as this approach seems, randomized trials of surveillance have not been performed in this special population, though observational studies performed on families with LS [66,67] and FAP [68] support the value of surveillance. These studies demonstrate a shift towards earlier stage at diagnosis and a corresponding reduction in CRC mortality among colonoscopy-detected cancers.
(Refer to the Major Genetic Syndromes section of this summary for more information about surveillance in high-risk populations.)

Rationale for screening

Widely accepted criteria (1–3 below) for appropriate screening apply as much to diseases with a strong genetic component (more than one affected first-degree relative or one first-degree relative diagnosed at younger than 60 years) as they do to other diseases.[69,70] Additional criteria (4 and 5) were added below.[71]
  1. A high burden of suffering, in terms of morbidity, mortality, and loss of function.
  2. A screening test that is sufficiently sensitive, specific, safe, convenient, and inexpensive.
  3. Evidence that treating the condition when it is detected early, by screening, results in a better prognosis than treatment after it is detected because of symptoms.
  4. Evidence on the extent to which the screening test and treatment do harm.
  5. The value judgment that the screening test does more good than harm.
Of these criteria, the first and second are satisfied in genetically determined CRC. The harms of screening (criterion 4), especially major complications of diagnostic colonoscopy (perforation and major bleeding), are also known. Evidence that early intervention results in better outcomes (criterion 3) is limited but suggests benefit. One study in the setting of LS found earlier stage/local tumors in the screened individuals.[65]

Identification of persons at high genetic risk of CRC

Clinical criteria may be used to identify persons who are candidates for genetic testing to determine whether an inherited susceptibility to CRC is present. These criteria include the following:
  • A strong family history of CRC and/or polyps (especially oligopolyposis).
  • Multiple primary cancers in a patient with CRC.
  • Existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of CRC, such as endometrial cancer.
  • Early age at diagnosis of CRC.
When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)
At this time, the use of mutation testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of mutations in the APC tumor suppressor gene and LS-associated MMR genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost effective.
Rather detailed recommendations for surveillance in FAP and LS have been provided by several organizations representing various medical specialties and societies. The following guidelines are readily available through the National Guideline Clearinghouse:
  • American Cancer Society.[72]
  • United States Multisociety (American Gastroenterological Association and American Society for Gastrointestinal Endoscopy) Task Force on Colorectal Cancer.[73]
  • American Society of Colon and Rectal Surgeons.[74]
  • National Comprehensive Cancer Network.[75]
  • Gene Reviews.
The evidence bases for recommendations are generally included within the statements or guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.

Primary Prevention of Familial CRC

Chemoprevention

Observational studies of average-risk people have suggested that the use of some drugs and supplements (NSAIDs, estrogens, folic acid, and calcium) might prevent the development of CRC.[76] (Refer to the PDQ summary on Prevention of Colorectal Cancerfor more information.) None of the evidence is convincing enough to lead expert groups to recommend these drugs and supplements specifically to prevent CRC, and few studies specifically enrolled people with an inherited predisposition for CRC. Although antioxidants are hypothesized to prevent cancer, a randomized controlled trial of antioxidant vitamins (beta carotene, vitamin C, and vitamin E) has shown no effect on CRC incidence.[77]
(Refer to the Interventions for FAP section and the Chemoprevention in LS section in theMajor Genetic Syndromes section of this summary for more information about chemoprevention.)

Modifying behavioral risk factors

Several components of diet and behavior have been suggested, with various levels of consistency, to be risk factors for CRC. (Refer to the PDQ summary on Prevention of Colorectal Cancer for more information.) These lifestyle factors may represent potential means of prevention.[76,78,79] Expert groups differ on the interpretation of the evidence for some of these components.
Little is known about whether these same factors are protective in people with a genetically increased risk of CRC. In one case-control study, low levels of physical activity, high caloric intake, and low vegetable intake were significantly related to cancer risk in people with no family history of CRC but showed no relationship in people with a family history, despite adequate statistical power to do so.[80]
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Colon Cancer Genes
  • Updated: July 28, 2016
Genetics of Colorectal Cancer (PDQ®)—Health Professional Version - National Cancer Institute
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