BRCA1 and BRCA2 mutations and the risk for colorectal cancer

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1 Clin Genet 2015: 87: Printed in Singapore. All rights reserved Review 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: /cge BRCA1 and BRCA2 mutations and the risk for colorectal cancer Sopik V, Phelan C, Cybulski C, Narod SA. BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet 2015: 87: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd, 2014 Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high-risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2 9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early-onset colorectal cancer, and offered colonoscopy at 3- to 5-year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter. Conflictofinterest The authors declare no conflict of interest. V. Sopik a,c.phelan b, C. Cybulski c and S.A. Narod a a Women s College Research Institute, Women s College Hospital, Familial Breast Cancer Research, 790 Bay Street, Toronto, Ontario M5G 1N8, Canada, b Department of Cancer Epidemiology, Moffitt Cancer Center, Magnolia Drive, Tampa, FL 33647, USA, and c Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland Key words: aspirin BRCA1 BRCA2 colonoscopy colorectal cancer prevention Corresponding author: Steven A. Narod, Women s College Research Institute, Women s College Hospital, Familial Breast Cancer Research, 790 Bay Street, 7th Floor, Toronto, Ontario M5G 1N8, Canada. Tel.: ; Fax: ; steven.narod@wchospital.ca Received 8 July 2014, revised and accepted for publication 29 August 2014 Mutations in several DNA repair genes contribute to the origin of many cancer types (1, 2). BRCA1 and BRCA2 are crucial proteins involved in homologous recombination, which is the most accurate method of double-stranded DNA break repair (3, 4). Germline mutations in BRCA1/2 are highly penetrant for breast cancer and ovarian cancer, conferring lifetime risks of up to 85% for breast cancer, and 40% (BRCA1) and 20% (BRCA2) for ovarian cancer (5, 6). BRCA mutations have also been associated with lymphoma, leukemia, melanoma, prostate, pancreatic, stomach and colorectal cancer (7, 8) but the magnitude of the relevant risks are not clear. Colorectal cancer is common and is often observed in hereditary breast and ovarian cancer families (9 11), but studies that have attempted to determine the excess incidence of colorectal cancer in BRCA mutation carriers have conflicting results and there are no guidelines for colorectal cancer screening among carriers (12). Through colorectal cancer screening, pre-cancerous lesions (adenomatous polyps) may be identified and removed, thus preventing invasive cancers. The gold standard is colonoscopy, because polyps can be removed with polypectomy during the initial procedure (13). The average lifetime risk for colorectal cancer is approximately 6% in North America, is similar in men and women, and 90% of sporadic colorectal cancers are diagnosed after age 50 (14). Established guidelines for individuals at average risk recommend screening colonoscopy once every 10 years beginning at age 50 (12, 15). One of the most important risk factors for colorectal cancer is a positive family history; approximately 10% of individuals in the general population have a first-degree relative affected by colorectal cancer and thereby carry a two- to four-fold increased risk for colorectal cancer (16). The risk is increased further if multiple first-degree relatives are affected, or if a relative 411

2 Sopik et al. Table 1. Prospective cohort, historical cohort and kin-cohort studies Reference Study design Study population Comparison population Exposed cases Estimated relative risk for colon cancer (95% CI) Phelan et al. (24) Kadouri et al. (23) Risch et al. (28) Struewing et al. (25) Prospective cohort 7015 carriers: 5481 BRCA1, 1474 BRCA2, and 60 with both Historical cohort 229 BRCA1 carriers with breast and/or ovarian cancer Kin-cohort 649 unselected ovarian cancer cases: relatives of 39 BRCA1 carriers and 21 BRCA2 carriers Kin-cohort 5318 Ashkenazi Jews: family histories of 120 founder mutation carriers (2.3%) rates (SIR) 769 non-carriers with breast and/or ovarian cancer 649 unselected ovarian cancer cases: relatives of 589 non-carriers 5318 Ashkenazi Jews: family histories of 4759 non-carriers 21: 8 early-onset BRCA1, age SIR: 4.76 (2.21 9)* 6 BRCA1 HR: 3.9 ( )* 13 BRCA1: 0.7 ( ) BRCA2: 2.5 ( ) 9 Incidence in families of mutation carriers: 8% In non-carriers: 11% SIR, standardized incidence ratio. *p < is diagnosed at age 50 or below. Approximately 20 30% of colorectal cancer cases occur in familial clusters (17), but only about 5% can be attributed to inherited conditions with a clear genetic definition (18), and for which guidelines have been established. These familial syndromes are caused by rare mutations in highly penetrant genes, which include MLH1, MSH2, MSH6 and PMS2 (for Lynch syndrome/hnpcc), APC (familial adenomatous polyposis), STK11 (Peutz Jeghers syndrome),mutyh (MUTYH-associated polyposis), PTEN (Cowden syndrome), BMPRIA and SMADH4 (juvenile polyposis). After a mutation is identified, carriers are enrolled in high-risk screening programs (12, 15). The majority of familial colorectal cancers are not explained by mutations in one of the high-risk genes. For these individuals, screening is primarily based on family history (12, 15). With advances in sequencing technology and the introduction of multi-gene panels, genetic testing is extending from only the inclusion of established high-risk genes to genes with moderate and unknown risks for colon (and other) cancers. Several clinical laboratories currently offer gene panel testing, but for many of the genes in a panel there are no guidelines for screening or prevention and counselling is difficult (19, 20). BRCA1 and BRCA2 are included in many cancer risk panels. Should BRCA1/2 be included on colorectal cancer risk panels? In some cases, a BRCA1 or BRCA2 mutation will be found among men and women with colon cancer and it is unclear how a positive test in this context could be used to improve the clinical management of colorectal cancer. To address these issues, the prevalence and penetrance of BRCA1/2 mutations for colorectal cancer must be determined, and efforts are required to educate clinicians and genetic counselors with accurate information on the associated risks and appropriate strategies for prevention. What is the penetrance of BRCA1/2 mutations for colorectal cancer? Different approaches have been used to determine the risk of colorectal cancer associated with BRCA1/2 mutations. These include studies of families with multiple cancers and of individual cases of colon cancer (7, 21 24). The approaches used in these studies included prospective cohort, retrospective cohort and kin-cohort designs (summarized in Table 1), association/ case control designs (Table 2), and family-based designs (Table 3). In general, most of the positive results (relative risks of two to four) were derived from studies of high-risk cancer families, whereas studies of unselected colon cancer patients generally found no significantly increased risks for either BRCA1 or BRCA2 (25 32). The validity of these studies must be assessed for precision and statistical power, which is determined in large part by the number of exposed cases identified (colon cases with mutations), and for bias, in order for conclusions to be made. The prospective cohort study The gold standard for estimating incidence is the prospective cohort study (33). Prospective studies have fewer potential sources of bias compared to retrospective studies, as none of the subjects have the outcome of interest at the time the study is initiated when baseline data are collected, and the events can be collected as they occur. However, given that both the exposure (BRCA1/2 mutation) and outcome (colorectal cancer) are rare, the size of a cohort required for an accurate determination of risk is large. To date, only one prospective cohort study has been conducted and published in 2014, the results of which indicate an approximately fourfold increased risk of early-onset colorectal cancer in female BRCA1 mutation carriers. In this study, Phelan et al. 412

3 BRCA1 and colorectal cancer Table 2. Case control studies in founder populations Reference Case population Control population Exposed cases Odds ratio (95% CI) Drucker et al. (26) Chen-Shtoyerman et al. (27) Neill et al. (32) Kirchhoff et al. (30) Suchy et al. (31) 87 Ashkenazi Jewish colorectal cancer cases: 3 carriers (3.5%) 225 Ashkenazi colorectal cancer cases: 4 carriers (1.78%) 1422 Ashkenazi colorectal cancer cases: 24 carriers (2.4%) 586 Ashkenazi colorectal cancer cases: 6 carriers (1.02%) 2398 Polish colorectal cancer patients: 10 BRCA1 carriers (0.42%); 7 carriers among 851 early-onset cases (0.82%) General population mutation frequency (2.5%) Population mutation frequency in Struewing et al. (2.26%) 1566 control subjects: 20 carriers (1.9%) 5012 control subjects: 118 carriers (2.35%) 4570 Polish controls: 22 BRCA1 carriers (0.48%) 3 Preliminary study 4 Not significant 24 All ages: 1.24 ( ) <65 years: 3.14 ( ) ( ) 10; 7 early-onset All ages: 0.8 <60 years: 1.7 ( ) *p < Table 3. Studies involving pedigree analysis of high-risk cancer families Reference Study population Comparison population Exposed cases Estimated relative risk for colon cancer (95% CI) Ford et al. (22) (BCLC) Brose et al. (21) Thompson and Easton (7) (BCLC) 33 families: 464 BRCA1 carriers and relatives 147 families from breast cancer risk clinic: 483 BRCA1 carriers (316 tested, 167 presumed carriers) 11,847 people from 699 families: 2245 BRCA1 carriers, 1106 non-carriers, 8496 unknown BCLC (8) 3728 people from 173 families: 681 breast/ovarian cancer patients, 471 unaffected BRCA2 carriers, 390 non-carriers, and 2186 unknown rates (SEER) rates (SEER) rates (SIR) rates (SEER) 19 BRCA1: 4.11 ( )* 19 BRCA1: 2.0 ( )* 14 BRCA1 Colon cancer: 2.03 ( )* Colorectal cancer: 1.25 ( ) Colorectal women only: 1.94 ( )* 8 BRCA2: 1.43 ( ) BCLC, Breast Cancer Linkage Consortium; SIR, standardized incidence ratio; SEER, Surveillance, Epidemiology, and End Results Program. *p < followed 7015 women with a BRCA1 or BRCA2 mutation, ascertained from 50 centers across the United States, Canada, and Europe (24). The women were followed for an average of 5.5 years (minimum of 2 years) for incident cases of colorectal cancer. The risk of colorectal cancer in BRCA1/2 mutation carriers was estimated with standardized incidence ratio (SIR), which is the ratio of observed cancer incidence in carriers to the expected number of colorectal cancer cases, based on population cancer rates. Twenty-one incident colorectal cancer cases were observed among all mutation carriers, which was similar to the 23.6 cases expected. However, eight of the 21 colorectal cancer cases in carriers were diagnosed in women younger than 50, compared to 2.10 expected in the general population (SIR: 3.81; 95% CI: ; p = 0.001). All eight colorectal cancer cases were identified in women with a BRCA1 mutation, compared to 1.68 expected (SIR: 4.76; 95% CI: ; p < 0.001). These data provide evidence that the risk of colorectal cancer may be increased by fivefold in female carriers of BRCA1 mutations younger than 50 years, but not in women with BRCA2 mutations or in women older than 50. However, the study had limited power to assess the risk of early-onset colorectal cancer in BRCA2 mutation carriers, because there were only 554 women with a BRCA2 mutation younger than 50 (compared to 2638 BRCA1 carriers aged 30 49). The cohort did not include men. The authors proposed that women with BRCA1 mutations should be counseled about their fivefold increased risk of early-onset colorectal cancer, 413

4 Sopik et al. which corresponds to a risk of about 1.0% to age 50, and should initiate colorectal cancer screening at the age of 40, every 3 5 years. The data for BRCA2 mutation carriers (and males) were insufficient to recommend earlier colorectal cancer screening. Pedigree review/family-based studies All other studies were retrospective designs, i.e. the outcome of interest (colorectal cancer) had already occurred when the study was initiated. Retrospective studies are often used to assess rare diseases; however, there is inherent potential for selection bias when subjects have already experienced the end point of interest; patients may be more likely to participate because of their diagnosis (resulting in overestimation of risk), or conversely, unable to participate if their diagnosis caused death or sickness (resulting in underestimation of risk). Cancer risks can also be estimated from the analysis of pedigrees of high-risk carrier families. These studies may be criticized for significant selection bias, because relative risks are derived from cancer incidence in families identified and referred because of multiple cancers. For example, if a physician was motivated to refer a patient for testing because of the presence of one or more colon cancers, the risk might be overestimated. In addition, the diagnosis of cancer in relatives may be purely based on the recall of the proband and this may result in misclassification. The Breast Cancer Linkage Consortium (BCLC) conducted several family-based studies to examine the risks of cancers other than breast and ovarian in BRCA1/2 mutation carriers. In the first study, Ford et al. in 1994 examined 33 families with evidence of linkage to BRCA1, and reported an estimated relative risk of 4.11 (95% CI: ) for colon cancer in BRCA1 mutation carriers (22). In a subsequent study, Thompson and Easton in 2002 extended the analysis to 699 families with at least one known BRCA1 mutation carrier, ascertained from 30 centers across Europe and North America (7). The cohort was comprised of 11,847 people, which included 2245 BRCA1 mutation carriers (18.9%), 1106 non-carriers (9.3%), and 8496 individuals with unknown mutation status (71.7%), and relative risks for cancers other than breast and ovarian were estimated with SIRs. Fourteen cases of colon cancer were identified among BRCA1 carriers, compared with 7.36 expected, corresponding to a significant, twofold increase in relative risk for colon cancer (RR: 2.03; 95% CI: ; p < 0.001). However, 76 cases of colon cancer were found in untested individuals, compared to expected, some of which were included in the risk estimate based on their statistical carrier probability. Additionally, there were inconsistencies in relative risk estimates for colon cancer, rectal cancer, and colorectal cancer, and for men vs women, suggesting that the proband s recall of cancer occurrence in her family may have been inaccurate. Brose et al. in 2002 examined cancer risks in 483 BRCA1 mutation carriers from 147 families identified through cancer risk evaluation programs in the United States (316 were tested BRCA1 carriers, and 167 were presumed carriers, based on pedigree analysis) (21). Nineteen cases of colorectal cancer were identified among presumed carriers, corresponding with a twofold increased relative risk for colon cancer in BRCA1 mutation carriers, as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. Although this study appears to be an independent support for a twofold increased risk of colon cancer in BRCA1 mutation carriers, 97 of the families from the clinic population, corresponding to 66% of the data, were included in the 699 families analyzed in the BCLC study. In 1999, the BCLC examined cancer risks in 173 families with evidence of linkage to BRCA2 (8). The final cohort of 3728 individuals included 681 individuals with breast or ovarian cancer, 471 unaffected individuals with BRCA2 mutations, 390 tested non-carriers, and 1186 individuals with unknown BRCA mutation status. The BCLC found eight colon cancer cases in probable BRCA2 mutation carriers, which was not significantly increased compared to 6.56 expected based on national cancer incidence rates (estimated relative risk 1.43; 95% CI: ). The number of exposed cases identified in each of these studies is low and the numbers are comparable to that of the prospective study. However, there are several limitations that may have affected the accuracy of risk estimates. The majority of individuals in these studies were never actually tested for BRCA1/2 mutations, and many of the colon cancers identified in the BCLC studies were later found not to be mutation carriers (S. Narod, unpublished results). Pathology reports were not obtained. When constructing the pedigrees, genetic counselors may have preferentially recorded affected individuals. Although families were not specifically ascertained based on the presence of cancer types other than breast and/or ovarian, there was probably a bias toward individuals with personal and family histories of cancer in general. This is because the initial motivation for participants to seek cancer risk assessment at the centers where families were ascertained was probably based on a strong presence of cancer in the family. Kin-cohort studies The kin-cohort study is an alternative, cross-sectional approach to assess the effect of a mutation that is less subject to bias than a family-based study. Samples of unselected patients with colon cancer are screened for mutation carriers, and the immediate family histories of mutation carriers are compared to family histories of non-carriers. Given that both carriers and non-carriers are identified in the same way and from the same unselected population, and that the mutation status was unknown by the proband at the time the information was collected, results are generally less biased than risk estimates from family-based studies. However, kin-cohort studies are still susceptible to information biases, limiting their potential to infer a causal relationship. Struewing et al. in 1997 screened 5318 Ashkenazi Jewish volunteers for the three Ashkenazi Jewish founder 414

5 BRCA1 and colorectal cancer mutations, 185delAG (BRCA1), 5382insC (BRCA1) and 6174delT (BRCA2), and compared the family histories of cancer in mutation carriers and non-carriers (25). Mutations were identified in 120 subjects (2.3%), but the relative risk for colon cancer in relatives of mutation carriers was not increased; nine BRCA1/2 mutation carriers reported a family history of colon cancer (8%) compared to 11% of non-carriers. Risch et al. in 2001 screened 649 unselected cases of ovarian cancer for BRCA1 and BRCA2 mutations and identified 60 mutation carriers among 515 invasive ovarian cancer cases (28). Relative risks were estimated by comparing cancer incidence in first-degree relatives of BRCA1/2 mutation carriers and non-carriers. There were three colorectal cancers identified among first-degree relatives of BRCA1 mutation carriers (BRCA1, RR: 0.7; 95% CI: ) and 10 cases identified among first-degree relatives of BRCA2 mutation carriers (RR: 2.5; 95% CI: ). Tulinius et al. screened 995 breast cancer patients in Iceland for the BRCA2 995del5 mutation (29). The family histories of 90 mutation carriers were compared to the family histories of 797 non-carriers, but no increased risk for colorectal cancer was found. Neither study had adequate statistical power to identify a modestly increased risk for colorectal cancer. Association/case control studies In association (case control) studies, individuals with colorectal cancer and control subjects without colorectal cancer from the same population are identified and DNA samples are studied for the mutation. Association/case control studies are specifically designed to estimate relative risks; however, due to the nature of the study design, they are unable to calculate absolute risks for disease (incidence). The lifetime risk associated with a mutation is estimated by multiplying the derived odds ratios with the general population risk. These studies depend on the ascertainment of unselected cases, and the appropriate selection of controls, failure of which can introduce significant selection biases. There is also a potential for survivorship bias if the cases are not identified shortly after diagnoses. The prevalence of BRCA1/2 mutations in the general US population is estimated to be approximately 1 in (34). In order to identify enough carriers for an accurate estimation of risk, most case control studies have been restricted to populations where the prevalence is increased, such as Ashkenazi Jews and Poland (26 28, 32, 33). Results from specific populations with founder mutations cannot necessarily be generalized to the entire carrier population; if the risk of colon cancer differs for different mutations, then the results may not be generalizable to carriers of other mutations. Case control studies conducted in founder populations are summarized in Table 2. Drucker et al. in 2000 screened 87 Ashkenazi Jewish colorectal cancer patients for the BRCA1/2 Ashkenazi Jewish founder mutations, and identified three carriers (3.5%), one in BRCA1 (185delAG) and two in BRCA2 (6174delT) (26). This prevalence was similar to the expected number of mutation carriers in Ashkenazi subjects without colorectal cancer. Chen-Shtoyerman et al. in 2001 screened 225 unselected Ashkenazi Jewish colorectal cancer patients in Israel for the presence of the three common BRCA Jewish founder mutations (27). Four carriers were identified (1.78%), which were not significantly different than the general Ashkenazi Jewish carrier frequency, as estimated by Struewing et al. (2.26%) (30). However, the control population was from Washington DC, and is probably not directly comparable to the carrier frequency identified in colorectal cancer cases from Israel. These association studies have conflicting results, but with only three and four exposed cases identified, and the inappropriate selection of controls, there is not enough accurate information for the conclusions to be considered valid. In a third case control study, Kirchoff et al. (2004) tested 586 unselected Ashkenazi Jewish colorectal cancer patients and 5012 Ashkenazi Jewish unaffected controls for BRCA1/2 founder mutations (30). Six mutation carriers were identified in cases (1.02%), and 118 mutation carriers were identified among control subjects (2.35%) (RR: 0.5; 95% CI: ). However, with only six exposed cases identified, this study has relatively small power. The control subjects were Jewish volunteers, who may have been motivated to participate because of a family history of cancer. Neill et al. (2004) tested 1422 unselected colorectal cancer patients and 1566 matched controls in Israel for the three BRCA Ashkenazi Jewish founder mutations (32). Twenty-four carriers were identified in cases (2.4%), which were not significantly increased compared to the 20 mutation carriers identified in control subjects (1.9%; OR: 1.24; 95% CI: ). However, stratification by age suggested that BRCA1/2 founder mutation carriers might be at an increased risk for developing early-onset colorectal cancer (OR for those younger than 65 years old: 3.14; 95% CI: ). Although not statistically significant, this finding provides support for an increased risk for early-onset colorectal cancer subsequently identified in the prospective study. Suchy et al. in 2010 conducted the largest case control study to date, testing 2398 unselected colorectal cancer patients from Poland, and 4570 unaffected controls, for three BRCA1 Polish founder mutations (C61G, 4153delA and 5382insC) (31). A BRCA1 mutation was identified in 10 colorectal cancer patients (0.42%) and in 22 control subjects (0.48%; OR: 0.8; p = 0.8). Seven of the ten mutations were identified among 851 patients that were diagnosed by age 60 (0.82%; OR: 1.7; p = 0.3). The mean age at onset of colorectal cancer in carriers was significantly decreased compared to non-carriers (57.0 years vs 64.0 years; p = 0.05). In this study, all the participants were enlisted within six months from diagnosis, limiting the potential for survivorship bias. Historical cohort study Historical cohort studies provide more direct estimates of risk (incidence) compared to case control studies, as they follow individuals from exposure to outcome, allowing for the calculation of hazard ratios. However, 415

6 Sopik et al. historical cohort studies remain susceptible to the biases inherent in a retrospective design, as the outcomes occur before enrollment. Kadouri et al. conducted a historical cohort study of 1098 Ashkenazi Jewish women affected with breast cancer and/or ovarian cancer, which included 229 BRCA1 mutation carriers, 100 BRCA2 mutation carriers, and 769 non-carriers (23). Six colorectal cancers were identified among BRCA1 mutation carriers (2.6%), two were identified among BRCA2 mutation carriers (2%) and 12 among non-carriers (1.6%). The incidence was significantly increased in BRCA1 mutation carriers compared to non-carriers, with a hazard ratio of 3.9 (95% CI: ; p = 0.018). BRCA1 carriers affected with colorectal cancer had an average age at onset that was 9 years older compared to non-carriers (71 in carriers, 62 in non-carriers, p = 0.61). These results are based on women with cancer, and restricted to the three BRCA1/2 Ashkenazi founder mutations, and therefore may not be representative of the entire carrier population. In summary, family-based studies have reported a two- to four-fold increase in the incidence of colorectal cancer among BRCA1 mutation families, but not among BRCA2 mutation families, while studies in unselected populations generally found no increased risk associated with BRCA1/2 founder mutations. There is a suggestion of an increased risk for early-onset colorectal cancer in the larger case control studies, which was subsequently confirmed in a prospective cohort of 7015 women with BRCA1 and BRCA2 mutations (24). In this prospective study, no increase was observed in the total number of incident colorectal cancers diagnosed in BRCA1/2 mutation carriers, compared to what would be expected in the general population; however, the incidence of colorectal cases diagnosed in women aged with a BRCA1 mutation was significantly increased (SIR: 4.76; 95% CI: ; p < 0.001). Interestingly, this is the highest risk estimate that has been reported for BRCA1 mutations in colorectal cancer. The data for BRCA2 mutation carriers and male BRCA1/2 mutation carriers are insufficient at present to conclude that there is any increased risk. Should BRCA1 be added to the colorectal cancer gene panel? The average risk for developing colorectal cancer by age 50 is approximately 0.2% (14). With an SIR of 4.76 in female BRCA1 mutation carriers aged 30 45, BRCA1 mutations are estimated to confer a risk for colorectal cancer of approximately 1% by age 50. No studies have been able to accurately determine the prevalence of BRCA1 mutations among colorectal cancer cases. Studies on Jewish and Polish populations have identified founder BRCA1 mutations in approximately 0.5 1% of colorectal cancer cases, but these were not statistically higher compared to the frequency of BRCA1 mutations in control subjects (28, 33). One approach that could be implemented to identify individuals at risk is to offer genetic testing of BRCA1 to all patients diagnosed with colorectal cancer, with the strategy of testing healthy relatives of the mutation carrier in order to prevent the occurrence of additional cancers in the family. However, the probability of finding a mutation carrier is likely to be very small. Additionally, with a penetrance of about 1% to age 50, it is unlikely that BRCA1-associated early-onset colorectal cancer would occur more than once in a family and the strategy of testing families with multiple cases of colorectal cancer for BRCA mutations would have limited impact. Achieving maximum impact would require preventing the first colorectal cancer in the family, which is only possible through population-based genetic testing. The preferred approach is to continue testing for BRCA1 only in the context of hereditary breast and ovarian cancer, and to counsel identified mutation carriers about their increased risk for early-onset colorectal cancer. Recommendations for screening and prevention Sporadic colorectal cancer typically develops over years (35), and progresses through well-defined stages of low-grade dysplasia to high-grade dysplasia to cancer (36). Dysplasia usually occurs within raised adenomatous polyps, allowing for their detection and removal. Colonoscopy is the preferred screening method, because it can screen for and remove adenomatous polyps in a single test, but the costs associated with colonoscopy restrict its use to individuals at increased risk. Other screening options, such as fecal occult blood testing, stool DNA testing, double contrast barium enema, computed tomographic colonography, and flexible sigmoidoscopy, are able to detect adenomatous polyps, but positive screening results always require follow-up with colonoscopy. Current guidelines for individuals at average risk recommend screening that begins at age 50, with either annual fecal occult blood tests, sigmoidoscopy every 5 years combined with fecal occult blood testing every 3 years, or screening colonoscopy every 10 years, and there is convincing evidence that screening with any of the three recommended tests reduces mortality in adults aged (37 39). Based on the increase in risk, individuals with a family history of colorectal cancer (e.g. one first-degree relative affected with colorectal cancer before age 60 or two first-degree relatives at any age) may be eligible for colonoscopy every 3 5 years beginning at age 40 (12). There may be distinct differences in the natural histories of sporadic and hereditary colorectal cancers, which would affect screening strategies. Molecular and genetic alterations may occur more rapidly or in an unconventional sequence. The natural history of BRCA1-associated colorectal cancers is not known. The most widely studied agent for chemoprevention of colorectal cancer is acetylsalicylic acid (aspirin). Data from several randomized control trials have shown that daily aspirin ( mg/day) for at least 5 years reduces the 20-year risk of death from colorectal cancer by 34%, and from all cancers by 20% (esophageal, pancreatic, brain, lung, stomach, prostate and colorectal cancer) (40). Aspirin in doses of 75 mg/day or higher reduced the 3- and 20-year incidence of all cancers, and 416

7 BRCA1 and colorectal cancer of colorectal cancer specifically, by 24% (41 43). In patients with Lynch syndrome, 600 mg/day of aspirin for at least 2 years was associated with a 60% reduction in the 5-year risk of colorectal cancer (44). Serious adverse events associated with regular aspirin use include gastrointestinal and cerebral bleeds; however, major bleeding events only occur 2.5% of the time with doses of 200 mg/day or greater, and 1.5% with doses under 100 mg/day (45, 46). Minimally effective doses required for colorectal cancer prevention may be as low as 75 mg/day (47). Due to the potential side effects, the US Preventive Services Task Force does not recommend aspirin for the chemoprevention of colorectal cancer in individuals at average risk or with a family history of colorectal cancer, but it may be recommended for individuals with personal history of colorectal cancer, FAP, or Lynch syndrome (48). BRCA1 mutation carriers are currently advised to take tamoxifen for the primary prevention of breast cancer (49, 50), and some physicians advise 1000 IU/day of vitamin D for the potential risk reduction of several cancers, including breast, ovarian, prostate and colorectal cancer (51, 52). Aspirin has also the potential to prevent several cancers associated with BRCA1 (breast, ovarian, prostate and colorectal cancer) making it an attractive agent for chemoprevention in BRCA1 mutation carriers, but the protective effect has not been proven (53, 54). For colorectal cancer prevention, we recommend that women with BRCA1 mutations be offered screening colonoscopies every 3 5 years beginning at age 40 and women older than 50 be screened as often as women at average risk. However, without knowledge of the natural history of BRCA1-associated colorectal cancers, it is difficult to predict the effectiveness of colonoscopy or to determine the optimal screening interval. Given the rarity of colon cancer among individuals with BRCA1 mutations, collecting the relevant clinical data will be challenging. Conclusions Mutations in BRCA1 confer an approximately fivefold increased risk for early-onset colorectal cancer, corresponding to a risk of about 1% to age 50. Screening colonoscopy is an effective method for colorectal cancer prevention with few side effects, and women with BRCA1 mutations should be offered colonoscopy every 3 5 years beginning at age 40. BRCA1-associated colorectal cancers have not been characterized in terms of their natural history and there is a possibility that pre-cancerous lesions would be less detectable by colonoscopy, or that cancer could develop between screenings. To potentially reduce this risk, carriers may be good candidates for chemoprevention with low-dose aspirin. 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