Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and 11 endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G>T, c.736_741del6ins11, c.862_863del, c.1688G>T, and c.2007–1G>A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable. Hum Mutat 27(5), 490–495, 2006. Published 2006 Wiley-Liss, Inc.
Abstract Introduction Breastfeeding has been inversely related to breast cancer risk in the general population. Clarifying the role of breastfeeding among women with a BRCA1 or BRCA2 mutation may be helpful for risk assessment and for recommendations regarding prevention. We present an updated analysis of breastfeeding and risk of breast cancer using a large matched sample of BRCA mutation carriers. Methods We conducted a case-control study of 1,665 pairs of women with a deleterious mutation in either BRCA1 ( n = 1,243 pairs) or BRCA2 ( n = 422 pairs). Breast cancer cases and unaffected controls were matched on year of birth, mutation status, country of residence and parity. Information about reproductive factors, including breastfeeding for each live birth, was collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate the association between ever having breastfed, as well as total duration of breastfeeding, and the risk of breast cancer. Results Among BRCA1 mutation carriers, breastfeeding for at least one year was associated with a 32% reduction in risk (OR = 0.68; 95% CI 0.52 to 0.91; P = 0.008); breastfeeding for two or more years conferred a greater reduction in risk (OR = 0.51; 95% CI 0.35 to 0.74). Among BRCA2 mutation carriers, there was no significant association between breastfeeding for at least one year and breast cancer risk (OR = 0.83; 95% CI 0.53 to 1.31; P = 0.43). Conclusions These data extend our previous findings that breastfeeding protects against BRCA1 -, but not BRCA2 -associated breast cancer. BRCA mutation carriers should be advised of the benefit of breastfeeding in terms of reducing breast cancer risk.
Thousands of individuals have undergone mutational analysis of BRCA1 and BRCA2. The Ohio State University Clinical Cancer Genetics program has identified 466 individuals from 289 families with a mutation in BRCA1 or BRCA2. Excluding Ashkenazi Jewish founder mutations, we observed 9 deleterious BRCA mutations five or more times in ostensibly unrelated families and another 13 mutations in 3-4 families. We hypothesized that some of the rarer recurrent mutations observed in our population were due to different branches of the same family being tested independently without knowledge of previous testing of relatives. We examined 90 pedigrees for individuals with the same mutations that were seen three or more times for shared reported family medical history or surnames. Familial links were made in four instances out of a total of 22 shared mutations despite the fact that individuals were not aware that another family member had been tested. As more individuals undergo BRCA testing, we propose that this phenomenon will become more common. Being unaware of previous testing in a family not only affects the risk assessment but also likely increases the costs associated with the genetic testing and subsequent cancer screening in many cases.
The objective of this study was to estimate the lifetime risk of breast cancer in women with a BRCA1 or BRCA2 mutation with and without at least 1 first-degree relative with breast cancer. A total of 2835 women with a BRCA1 or BRCA2 mutation were followed. Age- and gene-specific breast cancer rates were calculated. The relative risks of breast cancer for subjects with a family history of breast cancer, compared to no family history were calculated. The mean age at baseline was 41.1 years, and they were followed for a mean of 6.0 years. The estimated penetrance of breast cancer to age 80 years was 60.8% for BRCA1 and 63.1% for BRCA2. For all BRCA carriers, the penetrance of breast cancer to age 80 for those with no first-degree relative with breast cancer was 60.4% and 63.3% for those with at least 1 first-degree relative with breast cancer. The risk of breast cancer for BRCA carriers with no first-degree relative with breast cancer is substantial, and as a result, clinical management for these women should be the same as those for women with an affected relative.
Aim: To measure weight gain among unaffected women with a BRCA1 or BRCA2 mutation after undergoing an oophorectomy. Patients & methods: We compared the bodyweight of women with (n = 405) and without an oophorectomy (n = 741) at baseline as well as the rate of weight change prior to and following surgery among 1454 BRCA mutation carriers who had an oophorectomy. Results: There was a small and non-significant difference in bodyweight between BRCA mutation carriers who had an oophorectomy compared with those women who did not (151.5 vs 149.1 pounds; p = 0.26). There was an increase in bodyweight with increasing age, but this relationship did not differ prior to and following surgery (p comparing the slope parameters = 0.78). Conclusion: Oophorectomy is not associated with significant weight gain in high-risk women.
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