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Cancer risks and tumor types in male BRCA1 and BRCA2 mutation carriers are still unsettled. Cancer risks in men who were found to harbor a BRCA1 ( n  = 150) or a BRCA2 ( n  = 88) mutation or both ( n  = 2) were assessed by cross referencing with data on cancer occurrence in the Israeli National Cancer Registry. Incidence rates in mutation carriers were compared with men who were counseled, genotyped, and found not to harbor the familial mutation (true negative n  = 122), and with standardized incidence rates (SIRs). Of 210 cancer-free individuals at initial counseling, 11 cancers were diagnosed after a mean follow-up of 5.06 ± 4.1 years (1064 person/years) compared with 1/122 in a BRCA true-negative man. The SIR for all BRCA1/2 mutation carriers compared with the rates in the general population were elevated for pancreatic cancer [2.97 (95 % CI 1.83–4.29)] and breast cancer [16.44 (95 % CI 9.65–26.24)]. For prostate cancer these rates were 0.59 (95 % CI 0.4–0.84). Jewish BRCA1/2 mutation carriers are at an increased risk for breast and pancreatic, but not prostate cancer. These cancer risks and the consequent recommendations, if validated, should be transmitted to carriers at test result disclosure.

Background The incidence of cutaneous malignant melanoma continues to rise, and once the disease metastasizes it is almost inevitably fatal. We recently reported that a large miRNAs cluster on human chromosome 14q32, implicated in many types of cancers, is significantly down-regulated in melanoma. miR-377, one of the miRNAs located within this cluster, was studied here. Methods qRT-pCR was used to quantify miR-377 levels in melanoma cell lines and samples. Melanoma cell lines ectopically expressing miR-377 were generated by stable transfection, mRNA expression was assessed using mRNA arrays and protein expression was assessed by Western blot analysis. Potential targets of miR-377 were identified through luciferase reporter assays. Cellular proliferation, migration and soft-agar colony formation were monitored in control and miR-377-expressing cells using cell biology techniques. Results miR-377 is expressed in normal melanocytes but not in melanoma cell lines or samples. Its ectopic stable expression in melanoma cell lines decreased their proliferative and migratory capacity and their colony-forming capability. mRNA arrays of melanoma cells over-expressing miR-377 pointed to several down-regulated mRNAs that have putative binding sites for miR-377 in their 3′UTR, of which both E2F3 and MAP3K7 were found to be direct targets of miR-377. E2F3, a potent transcriptional inducer of cell-cycle progression, was found to be elevated in melanoma cell lines, but decreased following ectopic expression of miR-377. Ectopic miR-377 also led to a decrease in the activity of a reporter plasmid containing three E2F DNA-binding sites linked to a luciferase cDNA sequence, demonstrating that miR-377 down-regulates E2F3-induced transcription. MAP3K7 (known as TAK1), a serine/threonine kinase along the MAPK signaling pathway, was over-expressed in melanoma but decreased following ectopic expression of miR-377. MAP3K7 is involved in the activation of NF-κB. MiR-377 over-expression led to decreased activity of a reporter plasmid containing two NF-κB DNA-binding sites and to decreased output along the NF-kB signaling pathway. Conclusion Our results suggest that miR-377 is an important negative regulator of E2F and MAP3K7/NF-kB signaling pathway in melanoma cells; it is tempting to speculate that its silencing in melanoma promotes the tumorigenic and metastatic potential of the cells through activation of these pathways.

Background Whether breast cancer (BC) should be considered within the spectrum of tumors in Lynch syndrome (LS) is unsettled. Recently, MSH6 and PMS2 germline mutations have reportedly been associated with an increased BC risk and with hereditary breast and ovarian cancer (HBOC) phenotype. We assessed the rates of the recurring Ashkenazi Jewish (AJ) mutations in the MSH6 gene (c.3984_3987dupGTCA and c.3959_3962delCAAG) in AJ cases with seemingly sporadic BC or HBOC phenotype, who were negative for the founder AJ BRCA1 / 2 mutations. Methods All AJ individuals, affected with BC ≤ 70 years and/or ovarian cancer at any age who were counseled, genotyped and tested negative for the BRCA1 / 2 founder mutations between January 2010 and February 2018 at the Oncogenetics unit, Sheba Medical Center, were genotyped for the AJ mutations in MSH6 . Results Of 1016 genotyped participants (815 BC cases, 132 ovarian cancer cases, and 69 with more than one cancer), five carriers (0.49%) of the recurring AJ mutations in MSH6 were identified. All had BC, and two had personal history of additional cancers (pancreatic, endometrial, colorectal). The rate of MSH6 mutations was 0.93% (4/429) when considering only cases with a personal or first-degree relative with LS-related cancer, and 0.17% (1/587) of cases with second-degree relative or no family history of LS-related cancers ( p  = 0.087). Conclusions Our data suggest the spectrum of genotyped mutations in AJ BC patients with a personal or family history of LS-related cancers should be expanded. These data should be validated in other populations with a similar phenotype.

PurposeTo define the mutational spectrum of several candidate gene mutations in Israeli male breast cancer cases.MethodsMBC cases counselled at the Oncogenetics unit, Sheba Medical Center from January 1998 to June 2017 were included. Relevant clinical and oncological data and cancer phenotype were retrieved. All participants were genotyped for the predominant Jewish BRCA1 and BRCA2 germline mutations using a chip-based assay. Those who tested negative were further genotyped for three recurring mutations in CHEK2 (c.1100delC, p.S428F, p.I157T), and single mutations in the FANCM (c.5791C>T), and RAD51D (c.556C>T) genes, by direct sequencing. The ethics committee approved the study.ResultsOverall, 61 MBC were identified and genotyped, 41 (67.2%) were Ashkenazim, age at diagnosis was 58.1 ± 12.6 years, and 31 (50.8%) had a family history of cancer. Of genotyped individuals, one (1.6%) harboured the 185delAG* BRCA1 mutation, 7 (11.4%) the 6174delT*BRCA2 mutation and 2 (3.2%) other recurring mutations in BRCA2 (overall 10/61–16.4% BRCA1/BRCA2 mutation carriers). Of BRCA-negative cases, 3/51 (5.9%) carried the p.S428F *CHEK2 mutation. None was a carrier of the other genotyped mutations in CHEK2, FANCM or RAD51D.ConclusionBRCA1, BRCA2 and CHEK2 germline mutations contribute to inherited predisposition to MBC in Israel.

BackgroundHereditary breast cancer is predominantly associated with germline mutations in the BRCA1 or BRCA2 genes. A few recurring mutations in these genes were reported in ethnically diverse Jewish populations. Since 2013, most oncogenetic laboratories in Israel adopted a two-step approach for BRCA1/2 genotyping, where the first step is genotyping for 14 seemingly recurring mutations—first-pass genotyping. The aim of this study was to assess the yield of this targeted BRCA sequencing.MethodsClinical and genotyping data of all individuals who underwent oncogenetic counseling and first-pass BRCA genotyping at the Oncogenetic Service Sheba and Assaf Harofeh Medical Centers from 1 February 2013 to 30 June 2017 were reviewed. All study participants were unrelated to each other.ResultsOverall, 5152 oncogenetic tests were reviewed in the present study, of which 4452 had no a priori known familial mutation. The majority of participants (68.6%) were genotyped because of personal history of cancer; 20.6% were tested because of family history of cancer, and details for the remaining 10.7% were missing. Overall, 256/4452 (5.8%) carriers were detected, 141 BRCA1 and 115 BRCA2 mutation carriers. In 54% of cancer-free carriers, no clinically suspicious family history of cancer was ascertained.ConclusionsThe currently used scheme of first-pass genotyping in Israel seems to have a high yield of mutation detection even in the absence of a significant family history of cancer. The challenge is to optimize the currently used targeted panel of common mutations and adjust it to the accumulating new data in the Israeli population.

Purpose The contribution of genetic factors to cancer in non-Jewish populations in Israel is understudied. Yet the early, mostly premenopausal age at breast cancer diagnosis is suggestive of an inherited predisposition. Methods High-risk cancer cases of non-Jewish origin who were counseled at the Oncogenetics unit, Sheba Medical Center and the oncology institute at the Ziv medical center from January 1, 2000 to December 31 2016 were eligible. DNA extracted from leukocytes was subjected to massive parallel, next-generation sequencing using the Color Genomics platform. Data were analyzed for pathogenic and likely pathogenic mutations using existing pipelines. Results Overall, 68 cases, each representing a unique high-risk breast/ovarian family, were genotyped: 32 Druze, 26 Muslim Arabs, and 10 Christian Arabs. Fifty-nine had breast cancer (mean age at diagnosis 42.7 ± 7.6 years), and 9 had ovarian cancer (51.6 ± 9.7 years). Overall three pathogenic mutations one each in BRCA1, PALB2, and BRIP1 genes were detected mostly in Druze families. In addition, 29 variants of unknown significance were also detected, and in 36 cases no sequence variants were noted in any of the genotyped genes. Conclusion The contribution of the known cancer susceptibility genes to the burden of inherited breast/ovarian cancer predisposition in non-Jews in Israel is modest. Other genes or molecular mechanisms account for the familial breast/ovarian cancer clustering in this population.

Several algorithms have been developed to assess the risk of predicting BRCA mutation and breast cancer (BC) risk. The aim of this study was to evaluate the accuracy of these prediction algorithms in the Israeli population. Risk for developing breast cancer and the probability for carrying BRCA1/2 mutations using BOADICEA, BRCAPRO, IBIS, MYRIAD and PENN2 models were computed for individuals counseled and genotyped at the Oncogenetics unit in 2000 and 2005. The predicted mutation carriers and BC risks were compared with actual carrier rates by genotyping and BC diagnoses derived from the Israeli National Cancer Registry database. Overall, 65/648 (10%) study participants were BRCA1/2 mutation carriers. Of 373 cancer-free participants at counseling, 25 had breast cancer by 2016. BOADICEA and BRCAPRO performed best for predicting BRCA mutation (AUC=0.741, 0.738, respectively). No model was clinically useful in predicting breast cancer risk. BOADICEA and BRCAPRO outperformed the other tested algorithms in BRCA mutation prediction in Israeli women, but none was valuable in breast cancer risk prediction.

PurposeSeveral common genetic variants (single-nucleotide polymorphisms, SNPs) have been shown to be associated with breast cancer (BC) risk in the general population, and to modify BC risk for BRCA1 and BRCA2 mutation carriers. Co-localization of variable number of tandem repeats (VNTRs) with these BC-associated SNPS has not been comprehensively studied.MethodsCross referencing of genome-wide VNTRs with the known BC genome-wide association studies (GWAS) SNPs significantly associated with increased risk for developing breast cancer was carried out. Analysis was based on the overlap between the VNTRs and 10-kb windows around these BC-susceptibility SNPs.ResultsCross referencing of the 1.2 million TR with the 161 known BC-associated SNPs in the general population led to 690 matches. Of those, in 17 VNTRs, the SNP was within the VNTR. Analysis restricted to loci known to modify BC penetrance in BRCA1 (n = 31) and BRCA2 (n = 33) mutation carriers led to 139 and 170 co-localization matches, respectively. For these, none of the SNPs were within the VNTR. The distances between the SNPs and the VNTRs were not significantly different from what was expected to occur by chance alone (p = 0.61; p = 0.44; p = 0.25, respectively).ConclusionThere is no evidence that VNTRs co-localize with currently reported SNP tagged BC GWAS loci.

ObjectiveThe insulin-like growth factor I receptor (IGF-IR) and BRCA1 affect cell growth and apoptosis. Little information is available about BRCA1 activity on the IGF signaling pathway. This study evaluated the effect of BRCA1 on IGF-IR expression.MethodsBRCA1 and IGF-IR immunohistochemistry on archival tissues (35 uterine serous carcinomas [USCs] and 17 metastases) were performed. USPC1 and USPC2 cell lines were transiently cotransfected with an IGF-IR promoter construct driving a luciferase reporter gene and a BRCA1 expression plasmid. Endogenous IGF-IR levels were evaluated by Western immunoblotting.ResultsWe found high BRCA1 and IGF-IR protein expression in primary and metastatic USC tumors. All samples were immunostained for BRCA1—71% strongly stained; and 33/35 (94%) were stained positive for IGF-IR—2 (6%) strongly stained. No difference in BRCA1 and IGF-IR staining intensity was noted between BRCA1/2 mutation carriers and noncarriers. Metastatic tumors stained more intensely for BRCA1 than did the primary tumor site (P = 0.041) and with borderline significance for IGF-IR (P = 0.069). BRCA1 and IGF-IR staining did not correlate to survival. BRCA1 expression led to 35% and 54% reduction in IGF-IR promoter activity in the USPC1 and USCP2 cell lines, respectively. Western immunoblotting showed a decline in phosphorylated IGF-IR and phosphorylated AKT in both transiently and stably transfected cells.ConclusionsBRCA1 and IGF-IR are highly expressed in USC tumors. BRCA1 suppresses IGF-IR gene expression and activity. These findings suggest a possible biological link between the BRCA1 and the IGF-I signaling pathways in USC. The clinical implications of this association need to be explored.

Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse. To assess the contribution of E1317Q to CRC development in the Jewish population. A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined. The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation. In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.