© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
BRCA1 and BRCA2 Founder Mutations and the Risk of Colorectal Cancer
Affiliations of authors: Department of Internal Medicine, Division of Molecular Medicine and Genetics (BLN, JDB, LPT, SBG), Department of Epidemiology, School of Public Health (BLN, SBG), and Department of Human Genetics (SBG), University of Michigan Medical School, Ann Arbor, MI; Department of Community Medicine and Epidemiology, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel (GR); Clalit Health Services National Cancer Control Center, Haifa (GR, RA).
Correspondence to: Stephen B. Gruber, MD, PhD, MPH, Division of Molecular Medicine and Genetics, 4301 MSRB III, Box 0638, 1150 W. Medical Center Dr., University of Michigan, Ann Arbor, MI 48109-0638 (e-mail: sgruber{at}umich.edu)
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ABSTRACT |
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Background: Mutations in BRCA1 and/or BRCA2 (BRCA1/2) profoundly increase the risks of breast and ovarian cancers, but it is unclear whether mutations in these genes increase the risk of colorectal cancer. We investigated BRCA1/2 founder mutations and a family history of breast cancer as potential risk factors for colorectal cancer. Methods: In the population-based Molecular Epidemiology of Colorectal Cancer study in northern Israel, 1422 case patients with incident colorectal cancer, diagnosed between March 31, 1998, and December 31, 2002, and 1566 control subjects without colorectal cancer were genotyped for the BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT founder mutations. Genotypes and interview data from all case patients and control subjects and from only those of Ashkenazi Jewish descent (1002 case patients and 1038 control subjects) were used to calculate odds ratios [ORs] from logistic regression. Results: Twenty-four (2.4%) case patients and 20 (1.9%) control subjects carried one of the three mutations (OR = 1.24, 95% confidence interval [CI] = 0.68 to 2.26). A family history of breast cancer in a female relative was not associated with an increased risk of colorectal cancer, even after adjustment for the presence of a BRCA founder mutation (OR = 1.03, 95% CI = 0.75 to 1.41). Conclusions: Although weak associations cannot be excluded, Ashkenazi BRCA founder mutations do not confer a strongly elevated risk of colorectal cancer. Similarly, a family history of breast cancer does not appear to be a strong risk factor for colorectal cancer in this population.
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INTRODUCTION |
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Mutations in BRCA1 and/or BRCA2 (BRCA1/2) profoundly increase the risks of breast and ovarian cancers among women, but it is not clear whether mutations in these genes increase the risk of colorectal cancer. In 1994, the Breast Cancer Linkage Consortium reported that the risk of colorectal cancer in BRCA1 mutation carriers was statistically significantly increased (relative risk [RR] = 4.11, 95% confidence interval [CI] = 2.36 to 7.15) (1). A subsequent study of BRCA2 mutation carriers from the same group of investigators showed no statistically significantly elevated colorectal cancer risk associated with BRCA2 mutations (RR = 1.43, 95% CI = 0.79 to 2.58) (2). In a large population-based series of ovarian cancers, Risch et al. (3) identified an increased relative risk of colorectal cancer in first-degree relatives of BRCA2 mutation carriers but not in BRCA1 mutation carriers (for BRCA1 mutation carriers, RR = 0.70, 95% CI = 0.17 to 2.8; for BRCA2 mutation carriers, RR = 2.5, 95% CI = 1.0 to 6.3), compared with those without such mutations in a family member. Two recent articles, one by Thompson and Easton (4) and one by Brose et al. (5), analyzed portions of the Breast Cancer Linkage Consortium data to further describe the risks of cancers in BRCA1 mutation carriers. Thompson and Easton (4) reported a twofold increase in colon cancer risk (RR = 2.03, 95% CI = 1.45 to 2.85) but a statistically significantly decreased risk of rectal cancer (RR = 0.23, 95% CI = 0.09 to 0.59) when BRCA1 mutation carriers were compared with those without such a mutation. After combining the rectal and colon cancers, no statistically significantly increased risk of colorectal cancer in BRCA1 mutation carriers was evident (RR = 1.25, 95% CI = 0.91 to 1.72) compared with those without such a mutation. Brose et al. (5) compared the cumulative age-adjusted risk of colon cancer in BRCA1 mutation carriers (11%, 95% CI = 8.2% to 13.9%) with the Surveillance, Epidemiology, and End Results (SEER)1 Program population estimate of 5.6%, which suggested a twofold increased relative risk estimate. Currently, nationally recognized guidelines for the care of BRCA1/2 mutation carriers recommend informing the mutation carrier of a possible increased risk for colorectal cancer and encouraging the individual to follow screening guidelines for the general population (6).
Three founder mutations, BRCA1 187delAG (formerly known as 185delAG), BRCA1 5385insC (formerly known as 5382insC), and BRCA2 6174delT, have a combined prevalence exceeding 2% in Ashkenazi Jews, facilitating analyses of the phenotypic spectrum of tumors in gene carriers (7). In 1997, a large non–population-based study of Ashkenazi Jews from the Washington, DC, metropolitan area (7) compared the cancer histories of relatives of mutation carriers with those of relatives of non-carriers. This study, which used a kin–cohort design, found that the incidence of colon cancer among relatives of BRCA1/2 founder mutation carriers was not elevated compared with that among relatives of non-carriers. Two recent case patient series investigated the prevalence of these founder mutations in unselected case patients with colorectal cancer, and these case series report contradictory results and conclusions concerning the association between BRCA1/2 founder mutations and colorectal cancer (8,9). Compared with the 2% mutation prevalence found in the Struewing study (7), one case series found no statistically significantly increased founder mutation prevalence in case patients with colorectal cancer (1.78%), whereas the other study found a statistically significant increase in the prevalence of founder mutations among case patients with colorectal cancer (3.5%) (8,9).
Several studies have investigated the possibility of familial aggregation of breast cancer and colorectal cancer, and at least three show a positive association (10–12). Phipps and Perry (10) demonstrated an increased incidence of colorectal cancer in relatives of patients with familial breast cancer compared with that of relatives of patients with sporadic breast cancer. Nelson et al. (11) found that colon cancer incidence was increased among women with a family history of breast cancer, although this risk estimate did not achieve statistical significance. Slattery and Kerber (12) reported that men with a first-degree relative with breast cancer had an increased risk of colorectal cancer (odds ratio [OR] = 1.3, 95% CI = 1.02 to 1.66) and women with a first-degree relative with breast cancer also had an elevated risk of colorectal cancer (OR = 1.59, 95% CI = 1.25 to 2.03). Given the inconsistent results regarding the risk of colorectal cancer in BRCA1/2 mutation carriers, we conducted a planned interim analysis of the Molecular Epidemiology of Colorectal Cancer study. We investigated whether the three BRCA1/2 founder mutations and a family history of breast cancer are associated with the risk of developing colorectal cancer within a population-based case–control study of colorectal cancer.
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METHODS |
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Sample Collection
The Molecular Epidemiology of Colorectal Cancer study is an ongoing, population-based case–control study of case patients with pathologically confirmed, incident colorectal cancer diagnosed between March 31, 1998, and December 31, 2002, from the geographic region covered by the five major hospitals in northern Israel. Individually matched control subjects were identified from the Clalit Health Services database and matched for plus or minus 1 year of age, sex, the source clinic of the case patient, and ethnicity (Jewish versus non-Jewish). For each Molecular Epidemiology of Colorectal Cancer participant, blood, paraffin-embedded tumor specimens, and frozen tumor specimens (if available) were collected, and an in-person interview was performed. Between March 31, 1998, and December 31, 2002, 2409 case patients diagnosed with colorectal cancer were ascertained, and 2238 were approached and invited to participate. To date, 1438 case patients have consented to participate, and 1422 case patients completed in-person interviews and donated a blood sample. In addition, 1585 population-based control subjects without colorectal cancer consented to participate. These control subjects were identified from a list of individuals generated from the Clalit Health Services database who were matched by age, sex, clinic, and ethnicity (Jewish versus non-Jewish) to diagnosed case patients. This sampling strategy accounts for the slight overrepresentation of control subjects to case patients for this ongoing matched study. We elected not to exclude control subjects for whom we had data for this analysis, even when the case patient had not yet been recruited. A total of 1566 control subjects who completed an in-person interview and donated a blood sample were considered in this analysis. The 1585 control subjects who consented to participate included 53% of potentially eligible control subjects who participated when first approached, 22.4% of control subjects who were recruited from a pool of first-replacement control subjects, and 24.6% of control subjects who were recruited from second-replacement or higher-order control subjects. For matched analyses, the dataset was restricted to the 1217 matched pairs with complete genotyping and epidemiologic data. The study was approved by the Institutional Review Boards at the University of Michigan and Carmel Medical Center in Haifa. Written, informed consent was required for eligibility.
Family History of Cancer
Family histories of cancer were obtained by interviews of Molecular Epidemiology of Colorectal Cancer study participants. All children, siblings, parents, grandparents, aunts, and uncles were enumerated; for each relative, case patients and control subjects were asked to report whether that relative had ever been diagnosed with cancer. For each relative, up to three primary cancers, ages at diagnoses, and smoking history were recorded. Analyses reported are restricted to first-degree relatives (parents, siblings, and children). Pathology documentation of cancers among relatives was not systematically collected.
DNA Extraction and Genotyping
Genomic DNA was extracted from whole blood by use of a commercially available kit, according to the manufacturer’s protocol (Puregene DNA extraction kit; Gentra Systems, Research Triangle, NC). Genetic testing for BRCA1 187delAG was performed by restriction enzyme digestion, as previously described (13). BRCA2 6174delT was assayed by an allele-specific polymerase chain reaction as described (7). A modification of a published allele-specific oligonucleotide assay (14) was developed to genotype for BRCA1 5385insC. For the 5385insC polymerase chain reaction, each 20-µL reaction mixture contained 100 ng of genomic DNA, 10 mM Tris–HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, all four deoxynucleoside 5'-triphosphates (each at 200 µM), AmpliTaq DNA Polymerase (Applied Biosystems, Foster City, CA) at 0.05 U/µL, 330 nM primer 20F, and 330 nM primer 20R, with primer sequences from Struewing et al. (7). Thermal cycling included an initial denaturation at 95 °C for 5 minutes, then 35 cycles of a 30-second denaturation at 94 °C, a 1-minute annealing at 60 °C, and a 1-minute extension at 72 °C, with a final 10-minute extension at 72 °C. Allele-specific oligonucleotide hybridization was performed as previously described (14), with the following two differences: the hybridization and wash steps were done at 56 °C, the wild-type probe was 5'-ACCTTTCTGTCCTGGGATTC-3', and the mutant probe was 5'-ACCTTTCTGTCCTGGGGATT-3' (14). Genomic DNA from patients with breast cancer known to have one of the three mutations 187delAG, 6174delT, or 5385insC served as positive control for each assay, and genomic DNA samples from patients with breast cancer who did not have the mutation of interest were used as negative controls for each assay. Each assay was validated against a panel of 38 known samples, with 100% sensitivity and specificity. In addition, all positive 187delAG, 6174delT, and 5385insC samples were confirmed by sequencing with an ABI 377 sequencer (Applied Biosystems) through the University of Michigan DNA Sequencing Core facility. Samples were genotyped for APC I1307K polymorphism, as previously described (14), because this polymorphism might be a low-penetrance susceptibility allele for breast cancer and thus should be considered a potential confounder of the putative associations between BRCA1/2 mutations or a family history of breast cancer and the risk of colorectal cancer.
Statistical Methods
To compare demographic characteristics between case patients and control subjects, two-sided Student’s t tests and 
2 tests were performed with SAS version 8.02 (SAS Institute, Cary, NC). Genotypes and interview data from all case patients and control subjects and from only those of Ashkenazi Jewish descent (1002 case patients and 1038 control subjects) were used to calculate odds ratios from logistic regression. Unmatched and matched analyses used unconditional and conditional logistic regression, respectively. No substantive differences were observed between the matched and unmatched analyses, although the confidence intervals were wider for the matched data as a consequence of the smaller sample size of matched pairs.
In a kin–cohort analysis, we compared cancer risks among the relatives of BRCA1/2 mutation carriers and the relatives of BRCA1/2 mutation non-carriers. Each family member was considered to be at risk until the time of cancer diagnosis, death, or interview of the case patient or control subject. Cumulative cancer risk estimates were calculated with a Kaplan–Meier analysis and compared with the log-rank test (7,15,16). All statistical tests were two-sided.
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RESULTS |
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The demographic characteristics of case patients and control subjects are shown in Table 1. The proportions of men and women were similar between case patients and control subjects, and the mean age of case patients was within 1 year of the mean age of control subjects.
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Genotyping for BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT was successful for 99.7% of case patients and for 99.0% of control subjects. Twenty-four (2.4%) case patients and 20 (1.9%) control subjects carried one of the three mutations (OR = 1.24, 95% CI = 0.68 to 2.26). All mutation carriers were heterozygous, and no compound heterozygotes were identified. Among all 999 Ashkenazi Jewish case patients and 1028 Ashkenazi Jewish control subjects for whom genotyping was successful, BRCA1/2 mutations did not confer a statistically significantly increased risk of colorectal cancer, although weak associations could not be excluded (Table 2). Analyses stratified by individual mutation had limited power, especially for BRCA1 5385insC.
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After adjustment for potential confounders, the three Ashkenazi BRCA founder mutations did not confer a clinically meaningful or statistically significant risk for colorectal cancer when combined (OR = 1.21, 95% CI = 0.67 to 2.19) or when analyzed by individual mutation (Tables 3 and 4). Incorporating APC I1307K carrier status into the adjusted model did not measurably alter the risk (OR = 1.17, 95% CI = 0.64 to 2.13). Alternative models with these same covariates that included a family history of breast cancer in each type of first-degree female relative did not change these results (data not shown). A family history of breast cancer in a first-degree female relative was not associated with a measurable increased risk of colorectal cancer, even after adjustment for the presence of a BRCA founder mutation (OR = 1.03, 95% CI = 0.75 to 1.41). Matched analyses of 1217 pairs had similar results (Table 5).
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In unmatched, adjusted analyses restricted to the Ashkenazi Jews, our study detected no statistically significant difference between the risk of colon cancer and the risk of rectal cancer in BRCA1 and BRCA2 mutation carriers (OR for colon cancer = 1.14, 95% CI = 0.59 to 2.22; OR for rectal cancer = 1.55, 95% CI = 0.56 to 4.28) compared with non-carriers. After stratifying by sex, no statistically significant difference in the risk of colorectal cancer associated with BRCA1/2 mutations was observed in an unmatched, adjusted model (for women, OR = 1.21, 95% CI = 0.53 to 2.75; for men, OR = 1.17, 95% CI = 0.47 to 2.94; P for interaction = .93). Stratification by age in adjusted analyses also demonstrated no statistically significant difference in risk of colorectal cancer, although the point estimates suggest that BRCA1/2 founder mutation carriers might be at an increased risk of developing colorectal cancer at a younger age (for those <65 years old, OR = 3.14, 95% CI = 0.64 to 15.43; for those
65 years old, OR = 0.96, 95% CI = 0.48 to 1.91; P for interaction = .22). Within the Ashkenazi Jews, the cumulative risk of all cancers (except for breast and ovarian cancer) was statistically significantly greater in relatives of BRCA1/2 mutation carriers than in relatives of BRCA1/2 mutation non-carriers (Fig. 1, A, log-rank P = .047). Because gynecologic cancers are commonly misclassified, we also analyzed cumulative risk in relatives after excluding breast, ovarian, and endometrial cancer. Relatives of BRCA1/2 mutation carriers no longer had a greater cumulative risk of cancer than relatives of non-carriers (log-rank P = .23). Not surprisingly, the cumulative risk of breast and ovarian cancers was statistically significantly greater in relatives of BRCA1/2 mutation carriers than in relatives of non-carriers (Fig. 1, B, log-rank P<.001). Limited power existed to estimate cumulative risks of other cancer types, including colorectal cancer.
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Within the Ashkenazi Jews, a family history of breast cancer in a first-degree female relative was not associated with a strong risk of colorectal cancer (OR = 1.08, 95% CI = 0.75 to 1.56). Any increased risk of colorectal cancer associated with a family history of breast cancer is unlikely to be mediated by BRCA1 or BRCA2 because adjustment for BRCA1/2 founder mutations, number of first-degree female relatives with a history of breast cancer, age, and sex did not change these results (Tables 3 and 4). One case patient who carried the BRCA2 6174delT mutation reported a family history of breast cancer in a male relative. There were not enough case patients and control subjects reporting multiple relatives with breast cancer to detect a trend in the risk of colorectal cancer with increasing numbers of affected relatives. To examine whether the age distribution of relatives confounds any potential association between a family history of breast cancer and colorectal cancer development, we compared the mean ages of each type of first-degree relative among case patients and control subjects. No statistically significant differences were observed for any type of relative.
In unmatched, adjusted analyses stratified by BRCA founder mutation carrier status, no statistically significant difference in the risk of colorectal cancer associated with a family history of breast cancer in a first-degree female relative was observed within the Ashkenazi Jews. However, our study had limited power to address the potentially important interaction between BRCA1/2 founder mutation carrier status and breast cancer family history on the risk of developing colorectal cancer (for BRCA1/2 founder mutation carriers with a first-degree female relative with breast cancer, OR = 0.61, 95% CI = 0.11 to 3.37; for BRCA1/2 founder mutation non-carriers with a first-degree female relative with breast cancer, OR = 1.13, 95% CI = 0.77 to 1.65; P for interaction = .49).
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DISCUSSION |
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In this article, we report data from a population-based case–control study of colorectal cancer that explores whether BRCA1/2 mutations confer an increased risk of colorectal cancer. With the exception of the study by Risch et al. (3), previous studies drew data from high-risk families and nonsystematic series, which may not be representative of the population at risk. Therefore, current cancer risk estimates in BRCA1/2 mutation carriers are likely to be overestimated, which underscores the importance of measuring the cancer risks associated with BRCA1/2 mutations in population-based studies (7).
BRCA1 and BRCA2 founder mutations do not confer a risk for colorectal cancer as high as the fourfold increased risk previously reported (1). Although we cannot exclude increases in the risk of colorectal cancer related to BRCA1/2 founder mutations, we suggest that any risk is unlikely to be clinically significant. This conclusion extends the recent findings of Thompson and Easton (4), who reported that BRCA1 mutation carriers were not at a statistically significantly increased risk of colorectal cancer compared with non-carriers. Although that study (4) noted a statistically significant discrepancy between the risk of colon cancer and the risk of rectal cancer in BRCA1 mutation carriers, we detected no statistically significant difference between the risk of colon cancer and the risk of rectal cancer in BRCA1 and BRCA2 mutation carriers. Within the study by Thompson and Easton (4), stratification by sex revealed that female BRCA1 mutation carriers had a twofold increased risk of colorectal cancer (RR = 1.94, 95% CI = 1.21 to 3.10), whereas male BRCA1 mutation carriers had no increased risk of colorectal cancer (RR = 0.93, 95% CI = 0.6 to 1.44). Our study did not identify any statistically significant differences in the risk of colorectal cancer associated with BRCA1/2 mutations after stratifying by sex or age, although the risk estimates in age-stratified analyses suggested that BRCA1/2 mutation carriers might be more likely to develop colorectal cancer at a younger age.
Our results suggest that a family history of breast cancer is unlikely to be a strong risk factor for colorectal cancer, because a family history of breast cancer in a first-degree female relative was not associated with the risk of colorectal cancer. A large study by Slattery and Kerber (12) identified a weak, but statistically significant, increase in the risk of colorectal cancer given a family history of breast cancer. The confidence intervals that we report in this article encompass the point estimates reported by Slattery and Kerber (12); therefore, we cannot exclude a weak association between a family history of breast cancer and the risk of colorectal cancer.
Previous studies have suggested that the APC polymorphism I1307K might be a low-penetrance susceptibility allele for breast cancer and should be considered a potential confounder of the putative associations between BRCA1/2 mutations or a family history of breast cancer and the risk of colorectal cancer. In one study (17), APC I1307K carriers were more likely than non-carriers to have first-degree relatives with breast cancer, even after adjusting for BRCA1/2 founder mutation carrier status (OR = 1.4, 95% CI = 1.1 to 1.8). A large case series of Ashkenazi Jewish women with breast cancer found that the frequency of APC I1307K was higher among unselected Ashkenazi Jewish case patients with breast cancer than among Ashkenazi Jewish control subjects (18). In our study, APC I1307K did not appear to confound the relationships between colorectal cancer and BRCA1/2 founder mutations or a family history of breast cancer.
In our kin–cohort analyses, the cumulative risk of all cancers except breast and ovarian was statistically significantly greater in the first-degree relatives of BRCA1/2 mutation carriers than in the first-degree relatives of non-carriers. The statistically significant increase in risk is largely attributable to endometrial cancers, some of which may represent misclassified ovarian cancers because cancer diagnoses in relatives were not histologically confirmed.
Limitations of this study include underreporting and potential misclassification of family histories, possible ascertainment bias, and limited power to precisely measure smaller relative risks that are potentially important. Family history reports of affected relatives could not be confirmed and are likely to be imperfect. However, previous methodologic studies (19,20) have shown good correspondence between reported family histories of cancer and histologically confirmed diagnoses in first-degree relatives. A study from Utah (19) compared self-reported and database-linked family cancer histories to measure the accuracy of family history reporting in case–control studies; this study (19) found high sensitivities for breast (83%) and colorectal cancer (73%), with no consistent differences observed between case patients and control subjects. That study suggested that participants in case–control studies are able to report family histories of breast or colorectal cancer without observable recall bias, suggesting that underreporting and misclassification of family history in our study is likely to be nondifferential and would, therefore, attenuate any measured associations. Selection bias might exist if case patients chose to participate in our study because of a family history of cancer, especially breast or ovarian cancer. Because it was determined in two prior case–control studies (21,22) of breast cancer that case patients and control subjects did not differentially participate in research because of a family history of cancer, any participation bias would likely be nondifferential, again biasing our results toward the null. Given the sample size of 999 case patients and 1028 control subjects with BRCA1/2 genotyping data and a two-sided statistical significance level of 
= .05, our study achieved 73% power to detect a twofold increased risk of colorectal cancer associated with BRCA1/2 founder mutations, if we assume a BRCA founder mutation prevalence estimate of 2% within the Ashkenazi Jewish study participants. With the same sample size and statistical significance level, our case–control study provided 98.9% power to describe a twofold increase in the risk of colorectal cancer associated with a family history of breast cancer in a first-degree female relative. For this power calculation, the prevalence of a positive family history of breast cancer in a first-degree female relative was estimated at 5.8% in the Molecular Epidemiology of Colorectal Cancer control population.
Further research into BRCA mutations and a family history of breast cancer as independent risk factors for colorectal cancer may elaborate the contributions of rare inherited syndromes to the risk of both cancers. Muir–Torre syndrome, a variant form of hereditary nonpolyposis colorectal cancer, has been suggested to confer an increased risk of breast cancer, especially after menopause (23). Peutz–Jeghers syndrome is associated with an increased risk of breast and intestinal cancers (24) and, similarly, the phenotypic spectrum of cancer syndromes associated with the PTEN gene (for example, Cowden syndrome) demonstrates an increased risk of breast cancer and intestinal neoplasia (25). Therefore, it would be reasonable to consider a number of candidate genes in future analyses of genetic variation and the familial aggregation of breast and colorectal cancer.
To date, there is no consensus regarding whether BRCA1/2 mutations increase the risk of colorectal cancer. Although our study does not entirely resolve this controversy, it does provide evidence that Ashkenazi BRCA1/2 founder mutations are not associated with a clinically meaningful or statistically significantly increased risk of colorectal cancer. Furthermore, this study suggests that a family history of breast cancer is not associated with a strong risk of colorectal cancer and that any increased risk of colorectal cancer associated with a family history of breast cancer is unlikely to be mediated by BRCA1 or BRCA2. For BRCA1/2 mutation carriers, enhanced screening for colorectal cancer beyond the guidelines for the general population is not yet supported by the data.
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NOTES |
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1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.
Supported in part by Public Health Service grants RO1-CA81488 (from the National Cancer Institute to S. B. Gruber), T32 GM07863 (from the National Institute of General Medicine Sciences to B. L. Niell), and T32 HG00040 (from the National Center for Human Genome Research to B. L. Niell), from the National Institutes of Health, Department of Health and Human Services.
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Manuscript received July 1, 2003; revised November 3, 2003; accepted November 13, 2003.
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