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Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.

This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Background: The 1100delC CHEK2 allele has been associated with a 1.4-4.7 fold increased risk for breast cancer in women carrying this mutation. While the frequency of 1100delC was 1.1-1.4% in healthy Finnish controls, the frequency of this allele in a North American control population and in North American breast cancer kindreds remains unclear.

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...

BACKGROUNDIt has been suggested that BRCA‐associated breast carcinoma may often lack a detectable preinvasive phase. To investigate this hypothesis, the authors compared the prevalence of histopathologic lesions in prophylactic mastectomy (PM) specimens from women with BRCA mutations and in mastectomy specimens obtained at autopsy from an age and race‐matched comparison group without a known cancer predisposition.METHODSAll specimens from women with a deleterious BRCA1 or BRCA2 mutation who participated in an ongoing follow‐up study and underwent PM at Memorial Sloan‐Kettering Cancer Center between November 1, 1987 and May 31, 2001 were reviewed. For each case, breast tissue from two age and race‐matched women without a known cancer predisposition was also reviewed. The prevalence of benign, premalignant, and cancerous lesions was compared.RESULTSMastectomy specimens from 24 cases and 48 comparison subjects were reviewed. Ductal carcinoma in situ (DCIS), atypical ductal hyperplasia (ADH), and atypical lobular hyperplasia (ALH) were all more common in PM specimens from women with BRCA mutations than in those from the comparison group. The odds ratio for the detection of any high‐risk lesion (DCIS, lobular carcinoma in situ, ADH, or ALH) in specimens from BRCA mutation carriers was 12.7 (95% confidence interval, 3.1–52.4; P < 0.001).CONCLUSIONSLesions associated with an increased risk of subsequent malignancy are more common in PM specimens from women with BRCA mutations than in breast tissue obtained at autopsy from unaffected women without a known predisposition. This finding suggests that hereditary breast carcinoma has a preinvasive phase that may be detectable with aggressive surveillance. Cancer 2003;97:1601–8. © 2003 American Cancer Society.DOI 10.1002/cncr.11225

To investigate the developmental and regional expression of the NR1-subunit of the NMDA-receptor on the protein level, two polyclonal antisera [NR1(N) and NR1(C)] were raised against fusion proteins derived from the N- and C-terminal domain of the NR1-subunit, respectively. In Western blots of rat brain membranes, both antisera specifically recognized a single protein band with an apparent molecular size of 115 kDa. The regional distribution of the NR1-subunit immunoreactivity was analyzed in the developing and adult rat brain using sections blotted onto nitrocellulose membranes for immunostaining. With the NR1(N)-antiserum, strongest signals were detected in hippocampus, followed by cortex, striatum and thalamus, and weaker staining was observed in tectum, brainstem and cerebellum of adult brain. The NR1(C)-immunoreactivity exhibited a similar distribution, except that the staining in thalamus, tectum, brainstem and cerebellum was faint or virtually absent. The distinct pattern of NR1(N)- and NR1(C)-immunoreactivity arose during postnatal development. At birth, moderate staining with both NR1-subunit antisera was observed throughout the brain increasing strongly in most brain regions until postnatal day 21. In some brain areas, however, the NR1(C)-, in contrast to the NR1(N)-staining, decreased postnatally e.g. in thalamus, tectum and brainstem. The restricted staining intensity of the NR1(C)-antiserum in particular areas of adult and developing brain appears to reflect the emergence of C-terminal splice variants of the NR1-subunit which are not recognized by the NR1(C)-antiserum.