I nherited predisposition to cancer is a major contributor to the breast and ovarian cancer burden among people of Ashkenazi ancestry. Approximately 2.5% of all people of Ashkenazi Jewish descent carry one of three ancient (founder) mutations in BRCA1 or BRCA2 (185delAG or 5382insC in BRCA1 and 6174delT in BRCA2). [1][2][3] In a recent population based study, 29% of Jewish women with ovarian cancer were shown to carry one of these three founder mutations. 4 In a series of 220 high risk Ashkenazi breast cancer families, a founder BRCA mutation was detected in 44%. If ovarian cancer was present in the kindred, 73% of families segregated a founder BRCA mutation. 5 Despite the high proportion of hereditary breast and ovarian cancer attributed to founder mutations of BRCA1 or BRCA2 in this population, some Ashkenazi families with histories highly suggestive of an inherited cancer predisposition have been shown to segregate other (non-founder) mutations of BRCA1 6 or BRCA2. 7 Counselling of families considering full sequence BRCA genotyping is complicated by the limited information available regarding the incidence of these non-founder mutations in the Ashkenazi population.We present a series of Ashkenazi Jewish kindreds at hereditary risk for breast and ovarian cancer who do not segregate one of the three Ashkenazi founder mutations and who have undergone full sequencing of the coding regions and flanking intronic regions of BRCA1 and BRCA2. Using the BRCAPRO algorithm, we have estimated whether the prevalence of nonfounder BRCA1 and BRCA2 mutations in a genetic isolate (Ashkenazim) is consistent with the background rate in an admixed population, or if selective or other effects have led to a non-founder mutation rate lower than would be expected. METHODSRecords of all patients seen by the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1.6.95 to 30.6.01, who identified themselves as being of Ashkenazi Jewish descent, and who consented to participate in an ongoing study evaluating the clinical significance of germline BRCA mutations, were reviewed. Seventy patients with a personal history of breast or ovarian cancer who underwent full sequence evaluation of BRCA1 and BRCA2 after testing negative for the three Ashkenazi founder mutations were identified. Demographic information for these patients is summarised in table 1.Founder mutation testing was performed in the Diagnostic Molecular Genetics Laboratory at MSKCC using previously published methods. [8][9][10] In some cases, samples were split and were genotyped a second time at the University of Washington as part of an ongoing cohort study. Sequencing of the coding regions and flanking intronic regions was carried out by Myriad Genetics Laboratories as previously described.11 All deleterious mutations were confirmed by single amplicon DNA sequencing in the Diagnostic Molecular Genetics Laboratory at MSKCC.A three generation pedigree for each kindred was entered into the BRCAPRO 12-14 model using CancerGene interface (Version 3.3, Un...

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Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma (n = 1), breast (n = 1), colon (n = 1), renal (n = 1), melanoma and uterine (n = 1), prostate (n = 1), endometrial (n = 1), bladder (n = 1), and gastrointestinal stromal tumor (GIST) (n = 2). Immunohistochemical staining and assessment of patient tumors for second hits and loss of heterozygosity in SDHA confirmed GIST as an SDHA-associated tumor and suggests SDHA germline mutations may be a driver in neuroblastoma tumorigenesis.

About half of the familial breast cancer cases are found to bear mutations in the breast cancer susceptibility gene 1 (BRCA1). The majority of BRCA1 mutations produce a truncated protein and BRCA1-associated breast tumors exhibit a number of defined tumor phenotypes. The function of BRCA1 has been examined in gene knockout mice in which the nullizygous mice die early in utero, but this lethality can be partially rescued by a nullizygous p53 mutation. Wild-type BRCA1 protein binds to a number of cellular proteins, including DNA repair protein Rad51, tumor suppressor p53, RNA polymerase II holoenzyme, RNA helicase A, CtBP-interacting protein, c-myc, BRCA1-associated RING domain protein (BARD1), BRCA2 protein, etc. These proteins likely mediate the involvement of BRCA1 in DNA repair, transcriptional transactivation, and cell cycle control. Overall, BRCA1 protein may act as a converging vehicle for cell regulatory proteins to associate with. Therefore, mutations in BRCA1 may affect the composition of these complexes on which dysregulation of cellular functions with eventual development of malignancy is expected.

Most acute skin toxicities were mild. Our infection rate was higher than in prior studies that used interstitial brachytherapy. Cosmesis was good to excellent in most patients. Breast brachytherapy with the MammoSite catheter was well tolerated; further investigations of breast brachytherapy with this system are warranted.