Purpose: The Breast Cancer Linkage Consortium and other family-based ascertainments have suggested that male carriers of BRCA mutations are at increased risk of prostate cancer. Several series looking at the frequency of BRCA mutations in unselected patients with prostate cancer have not confirmed this finding. To clarify this issue, we conducted a large case-control study.Experimental Design: Blood specimens from 251 unselected Ashkenazi men with prostate cancer were screened for the presence of one of the three common Ashkenazi founder mutations in BRCA1 and BRCA2. The incidence of founder mutations was compared with the incidence of founder mutations in 1472 male Ashkenazi volunteers without prostate cancer using logistic regression analysis after adjusting for age.Results: Thirteen (5.2%) cases had a deleterious mutation in BRCA1 or BRCA2 compared with 28 (1.9%) controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was associated with the development of prostate cancer (odds ratio, 3.41; 95% confidence interval, 1.64 -7.06; P ‫؍‬ 0.001). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio, 4.78; 95% confidence interval, 1.87-12.25; P ‫؍‬ 0.001), whereas the risk in BRCA1 mutation carriers was not significantly increased.Conclusions: BRCA2 mutations are more likely to be found in unselected individuals with prostate cancer than age-matched controls. These results support the hypothesis that deleterious mutations in BRCA2 are associated with an increased risk of prostate cancer.

Mutations in BRCA1 and BRCA2 that predispose to breast and ovarian cancer are detected in approximately 2.5% of the Ashkenazi Jewish population. To explore whether carriers of Ashkenazi founder mutations in BRCA1 or BRCA2 have an increased risk for colorectal cancer, we screened 586 unselected Ashkenazi Jewish case patients with colorectal cancer for the three common founder mutations in BRCA1 and BRCA2. We identified six carriers (1.02%) among these case patients. After adjusting for age at diagnosis and sex by use of logistic regression analysis, we compared the incidence of carriers in this group of 586 case patients with that of 5012 Ashkenazi Jewish control subjects without a known history of colorectal cancer. The presence of a founder BRCA mutation was not associated with the risk of colorectal cancer (relative risk = 0.50, 95% confidence interval = 0.22 to 1.14). We thus recommend that counseling for colorectal cancer screening and prevention in individuals with BRCA mutations be based on the personal and family history of colorectal cancer or associated syndromic malignancies.

Dear SirIn a recent study published in the International Journal of Cancer, Fleischmann et al. 1 described the results of screening for germline mutations in the human homolog of the E. coli mutY gene (MYH) in a series of 358 individuals affected with early-onset colorectal cancer (CRC), arbitrarily defined as a diagnosis before age 56, and 354 control individuals. In Caucasians, the 2 MYH mutations Y165C and G382D, identified in a subset of familial adenomatous polyposis (FAP) patients who lack mutations in the APC gene, are by far the most frequent known disease-causing mutations. 2,3 With respect to these mutations characterized previously, one CRC case carried biallelic MYH mutations (0.3%), and 5 CRC cases (1.4%) and one control (0.3%) carried monoallelic MYH mutations. Even though the frequency of carriers of monoallelic MYH mutations in CRC cases was not statistically different from the frequency in controls, the authors suggested that MYH heterozygotes might be at increased risk of developing CRC. In the present study, we have similarly assessed the frequencies of diseasecausing MYH mutations in 555 CRC cases and 918 controls.A consecutive series of individuals affected with CRC was identified, consisting of 555 individuals who visited the oncology clinic at Memorial Hospital in New York City. 4 Blood specimens were obtained regardless of ethnic origin and religion from 2002 to present. Before permanent anonymization of these samples, primary CRC diagnosis was confirmed by inspection of the electronic pathology record, and gender, religion, ethnic origin, history of chemotherapy, date of birth, age at diagnosis and date of diagnosis were recorded. DNA samples were prepared from blood as described previously. 5 Collection of these samples was performed under the auspices of an IRB-approved protocol.Controls (918) were obtained from a cohort study of over 17,000 volunteers of varying ethnic backgrounds, ages 30 -69, unaffected by cancer, and ascertained from 2000 -2002 at hospitals and blood donation centers that are geographically close to Memorial Hospital. 6 To ensure comparability, controls were chosen so that numbers of persons in each age, ethnic origin and religion group were approximately equal. Subjects provided informed consent for use of their de-identified DNAs for cancer genetics research.The Y165C mutation was detected in sequences amplified by polymerase chain reaction by pyrosequencing and the G382D mutation by restriction enzyme digestion with BglII. Because the 466delE mutation was recently described as disease-causing in some Italian familial FAP and attenuated FAP families, 7 we also screened for this mutation by direct sequencing. All mutation carriers were confirmed by direct sequencing. Odds ratios and exact confidence intervals were calculated using StatXact (Cytel software corporation, Cambridge, MA). Exact tests for Hardy-Weinberg equilibrium were performed for each mutation and for both mutations together using SAS version 9.0 (SAS Institute Inc., Cary, NC). Power calculations fo...

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited colorectal cancer syndrome attributable to mutations in one of several DNA mismatch repair genes, most commonly MLH1 and MSH2 . In certain populations, founder mutations account for a substantial portion of HNPCC. In this report we summarize the literature and our personal experience testing for a specific founder mutation in the Ashkenazi Jewish population, MSH2*1906G > C , also known as A636P. Although rare in the general population, the A636P mutation is detected in up to 7% of Ashkenazi Jewish patients with early age-of-onset colorectal cancer, and may account for up to one third of HNPCC in the Ashkenazi Jewish population. In addition, we summarize our initial experience with a prospective A636P testing protocol aimed at Ashkenazi Jewish patients at high or intermediate risk for harboring the A636P mutation.

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