Affiliation of authors: Clinical Genetics Service, Department of Medicine (TK, NDK, HH, PK, CP, HR, KN, NAE, KO), and Department of Epidemiology and Biostatistics (JMS), Memorial Sloan-Kettering Cancer Center, New York, NY.
Correspondence to: Kenneth Offit, MD, MPH, Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 192, New York, NY 10021 (e-mail: offitk{at}mskcc.org)
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ABSTRACT |
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Pathology records were reviewed to ascertain all individuals who identified themselves as Jewish and underwent a primary resection for colorectal cancer between March 31, 1994, and February 4, 2002, at Memorial Sloan-Kettering Cancer Center (MSKCC). All cases were confirmed by review of the surgical pathology report. We identified 430 tissue blocks and cut four to six tissue sections, 10 µm thick, from each block. The case patient's sex and age at diagnosis were coded and recorded. Identifying links were then destroyed. This protocol was approved by The MSKCC Institutional Review Board (IRB). Under a separate IRB-approved protocol, samples were obtained for anonymous germline DNA analysis from 204 consecutive Jewish individuals with a pathologically confirmed primary colorectal malignancy diagnosed between April 24, 2000, and August 27, 2002. After exclusion of 48 case patients who were also ascertained in the pathology review, blood specimens were coded with the case patient's sex and age of diagnosis, and identifying links were destroyed.
For tissue block samples, paraffin was removed by extraction with octane, and DNA was extracted with a PUREGENE DNA isolation kit (Gentra, Minneapolis, MN). For blood samples, DNA was purified with a QIAamp Blood DNA Midi kit (Qiagen, Valencia, CA). Genotyping the founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 was done with the following oligonucleotide primers flanking the mutation loci: 185delAG forward = 5'-CATTAATGCTATGCAGAAAATCTTCG-3' and 185delAG reverse = 5'-CTTACTAGACATGTCTTTTCTTCCC-3'; 5382insC forward = 5'-GTCCAAAGCGAGCAAGAGAATCTC-3' and 5382 insC reverse = 5'-GAATTCGAGACGGGAATCCAA-3'; 6174delT forward = 5'-TACTTGTGGGATTTTTAGCCAAGC-3' and 6174delT reverse = 5'-GTGAGCTGGTCTGAATGTTCGTTA-3'. Polymerase chain reaction (PCR) products were analyzed by amplification-created restriction enzyme site analysis for restriction enzymes TaqI (185delAG), DdeI (5382insC), and BstXI (6174delT) (14). Carriers were identified by comparing the test digest with digests of PCR analyses from previously verified BRCA1 and BRCA2 carriers. Sensitivity of this method of genotyping for Ashkenazi mutations by use of restriction endonucleases is comparable to sequencing (15,16), and frequencies of BRCA1 founder mutations in case patients with early-onset breast cancer were also comparable when the DNA was derived from lymphocytes or paraffin-embedded tissues (17,18).
Control subjects were 5012 self-identified Jewish volunteers recruited from advertisements in the Washington, DC, area. These control subjects were tested for the three Ashkenazi founder mutations, they did not have a history of colorectal cancer, and they had data available on BRCA mutation status (3). The age- and sex-specific rates were provided by the authors of this study. A logistic regression model was used to estimate the relative risk for cancer associated with BRCA mutation, after adjusting for age and sex by treating them as additional covariates in the model (19).
Ashkenazi founder mutations were identified in a total of six (1.02%) of 586 specimens. Among these case patients, two (0.34%) were carriers of BRCA1*185delAG, one (0.17%) was a carrier of BRCA1*5382insC, and three (0.51%) were carriers of BRCA2*6174delT. In the control group, 118 carriers of a BRCA1 or BRCA2 mutation were identified. Sex (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 0.89 to 1.30) was not associated with risk for colorectal cancer, by logistic regression analysis. After adjusting for age (OR = 1.07, 95% CI = 1.06 to 1.08), BRCA mutation status was not statistically significantly associated with the risk of colorectal cancer (RR = 0.50, 95% CI = 0.22 to 1.14; P = .10), by logistic regression analysis.
The current study is, to our knowledge, the largest series to date that has examined the incidence of BRCA1 and BRCA2 mutations in Jewish individuals with pathologically confirmed colorectal cancer. A study of 136 consecutive Israeli Jewish patients with colorectal cancer documented a slightly elevated risk of colorectal cancer in carriers of BRCA1 and BRCA2 mutations (20), but another series of 225 unselected Jewish patients with colorectal cancer did not confirm this association (12). The lack of association in the present series of 586 case patients makes it unlikely that the presence of a BRCA founder mutation has a substantial impact on the incidence of colorectal cancer.
There are several limitations in our study design that could potentially affect our results. A bias could have been introduced if the frequency of BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population in Washington, DC, was not reflective of the frequency of founder mutations in other Ashkenazi Jewish populations. The founder mutation carrier frequency from the Washington, DC, area study, however, was consistent with other large series from the United States (21) and with the observed frequency of the BRCA2 founder mutation in our study of a New York City cohort of patients undergoing prenatal genetic testing (4). The population frequencies of the three Ashkenazi founder mutations ranged from 2.3% to 2.7% among 8172 individuals (3,21); similarly, the frequency of BRCA2 6174delT was 0.9% in our series of 1255 individuals in New York City compared with 1.1% in the control series used in this study. Although these results support the appropriateness of historical control subjects from the Washington, DC, area in this study, it is important to note that, in both the case patients and the control subjects, individuals identified themselves as Jewish. Although the vast majority of Jews in the United States (approximately 90%) are of Ashkenazi Jewish ancestry, it is possible that a higher or lower proportion of Ashkenazi Jews in the case patients and control subjects could have resulted in a bias. A bias could also have been introduced by the use of a hospital-based series of patients with colorectal cancer rather than a population-based series. Such a bias would be evident if the BRCA-linked colorectal tumors had clinical features different from sporadic tumors, possibly leading to their over- or under-representation in a cancer referral center. Although such features have not been documented for BRCA-linked colorectal cancers, patients with BRCA-linked ovarian cancers have a superior prognosis (16). Such a finding might explain the under-representation of such patients in a cancer referral center and may account for the slight, statistically nonsignificant trend toward an increased prevalence in BRCA2 mutations observed in a recent population-based series of patients with colorectal cancer (22). Another plausible reason for the discrepancy between our results and the family-based analysis is misclassification of tumors in family members used for the family-based series. Because all cancers in this series were pathologically confirmed, this report does not have this limitation. Finally, families with BRCA1 and BRCA2 mutations included in prior family-based series may have been biased to include patients with sporadic colorectal cancer as well as other tumor types, leading to an apparent increased incidence of these tumors in these kindreds.
With regard to the generalizability of these findings, the three Ashkenazi founder mutations, like the vast majority of BRCA1 and/or BRCA2 mutations, cause premature protein truncation. Because there is some evidence of genotypephenotype associations for certain BRCA2 mutations (23), it is possible that the findings of studies of these three mutations may not be generalizable and that other BRCA1 and/or BRCA2 mutations may be associated with increased susceptibility to colorectal cancer.
Although other genetic mechanisms, notably the mutations APC*I1307K and possibly CHK2*1100delC, have been associated with familial breast and colorectal cancer (2426), this study finds no evidence that carriers of founder BRCA1 or BRCA2 mutations are at a statistically significantly increased risk of colorectal cancer. Given the lack of evidence for a younger age at onset of colorectal cancer observed in prior series, the most prudent approach to colorectal cancer screening and prevention in BRCA-associated kindreds continues to include colon screening beginning at age 50 years or earlier, depending on the familial or personal history of colorectal cancer or colorectal adenomas.
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NOTES |
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We thank the Washington Ashkenazi Study investigators, who provided the raw data files, including age- and sex-specific rates needed for the analyses in this brief communication.
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Manuscript received July 7, 2003; revised October 29, 2003; accepted November 4, 2003.
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