Inherited mutations in BRCA1 and BRCA2 lead to significantly increased risks of breast and ovarian cancer. We used epidemiologic methods to evaluate the relative risks of breast cancer vs. ovarian cancer among women of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 or BRCA2. The cancer of a family's index case (i.e., breast cancer vs. ovarian cancer) was significantly associated with site-specific risks of cancer in relatives known to carry mutations in BRCA1 or BRCA2. Specifically, breast cancer risks were higher among relatives of breast cancer index cases compared with relatives of ovarian cancer index cases [hazard ratio (HR) ‫؍‬ 3.0, P < 0.001 for BRCA1 carriers and HR ‫؍‬ 4.8, P ‫؍‬ 0.017 for BRCA2 carriers], and ovarian cancer risks were higher among relatives of ovarian cancer index cases compared with relatives of breast cancer index cases (HR ‫؍‬ 7.2, P ‫؍‬ 0.001 for BRCA1 carriers and HR ‫؍‬ 15.8, P ‫؍‬ 0.018 for BRCA2 carriers). Breast and ovarian cancer risks also increased with more recent year of birth. For each later decade of birth, risk increased 1.2-fold (P ‫؍‬ 0.03). Effects of cancer site of the index case and of birth cohort were independent. These results suggest that both genetic and nongenetic factors modify cancer risks among BRCA1 and BRCA2 mutation carriers, and that genetic modifiers and other familial factors may influence risk specifically for either breast or ovarian cancer.breast cancer ͉ ovarian cancer ͉ penetrance ͉ hereditary cancer I n the decade since BRCA1 (MIM 113705) and BRCA2 (MIM 600185) were identified as susceptibility genes for breast and ovarian cancer, testing of these genes has become part of clinical practice, and thousands of women worldwide have been identified as carriers of mutations in BRCA1 or BRCA2. Women with cancer-predisposing mutations are offered intensive surveillance for early cancer detection and͞or preventive measures. Although prevention of breast and ovarian cancer in carriers is highly effective, it primarily involves prophylactic surgery: oophorectomy and risk-reduction mastectomy (refs. 1 and 2 and reviewed in ref.3). In considering the best course of action for mutation carriers, it is essential to have accurate estimates of possible outcomes that include all genetic and nongenetic factors influencing risk.Breast cancer risks associated with BRCA1 and BRCA2, and ovarian cancer risk associated with BRCA1, have been shown to be higher in more recent birth cohorts (4-6). These secular (time) trends likely reflect nongenetic influences because risk changed within families among individuals with the same mutations. Meta-analysis further suggested that cancer risk among BRCA1 and BRCA2 carriers was influenced by the site of cancer (i.e., breast cancer or ovarian cancer) in the index case (5). This observation suggested that genetic modifiers, alleles of genes other than BRCA1 or BRCA2, might affect outcome in carriers of BRCA1 or BRCA2 mutations.The goal of this study was to investigate the influences of cancer site in the index case ...

Little is known about the effects of immunosuppression on patients with hereditary nonpolyposis colorectal cancer (HNPCC). We describe a kidney transplant recipient with unrecognized Muir-Torre syndrome in whom the administration of a tacrolimus-based regimen led to the eruption of multiple sebaceous tumors. The patient was later found to harbor an MSH2 mutation. Switching to a sirolimus-based regimen resulted in arrest of the disease. When the patient was switched back to tacrolimus, new facial lesions rapidly appeared. Switching again to sirolimus resulted again in halting the appearance of new lesions. This finding is in line with the known antiangiogenic activity of sirolimus and reports on the regression of cutaneous Kaposi's sarcoma in kidney transplant recipients switched from another immunosuppressive regimen to sirolimus. Further studies on the potential use of sirolimus for the treatment of de novo tumors in immunosuppressed kidney transplant recipients with HNPCC are warranted.

The Jews are an ancient and unique group of people linked by language, religion and customs in spite of their major geographical shifts, expulsions, forced conversions and massacres throughout their entire history. As a result of these historical events that led to repeated migration, the Jewish people became dispersed into various ethnic sub-groups. Between these ethnic groups exists heterogeneity, as well as some similarities, to the populations amongst whom they lived. Rare genetic diseases have been reported to be prevalent among the different groups of Jews, which for the most part can be explained by random genetic drift together with intra-familial marriages. In this publication, we will briefly discuss the origin of the various ethnic groups and some of the genetic diseases commonly found in them, with emphasis on the Ashkenazim, their prevalent genetic diseases and cancer susceptibility.

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.