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The frequency of BRCA1 and BRCA2 mutations is higher in Israel than in almost all other countries. One strategy to reduce the burden of hereditary breast and ovarian cancers is to offer genetic testing followed by risk-reducing surgery (mastectomy and salpingo-oophorectomy) for mutation carriers. The extent to which Israeli women who carry mutations undergo these surgeries is not well characterized. Israeli women who are BRCA1 or BRCA2 mutation carriers and followed at a single high-risk clinic were asked to complete a questionnaire detailing their clinical histories at the time of genetic results disclosure and a follow-up questionnaire was completed 18 or more months thereafter. A total of 205 mutation carriers completed the questionnaires. Of 170 women with no cancer history, 84 (49%) had a risk-reducing bilateral salpingo-oophorectomy and 22 (13%) had a risk-reducing mastectomy. Five of 35 (14.3%) women with breast cancer opted for contralateral mastectomy. Approximately one half of Israeli women with a BRCA1 or BRCA2 mutation opt for risk-reducing oophorectomy, but the rate of risk-reducing mastectomy is only 13%. [ABSTRACT FROM AUTHOR]

Purpose: Several recurring pathogenic variants (PVs) in BRCA1/BRCA2 and additional cancer susceptibility genes are described in the ethnically diverse Israeli population. Since 2019, testing for these recurring PVs is reimbursed unselectively for all patients with breast cancer (BC) in Israel. The aim was to evaluate the yield of genotyping for these PVs in non-Ashkenazi Jewish (AJ) patients with BC diagnosed ≥age 50 years., Methods: Clinical and genotyping data of all patients with BC undergoing oncogenetic counseling at the Oncology Institute at Sheba Medical Center from June 2017 to December 2023 were reviewed., Results: Of 2706 patients with BC (mean age at diagnosis, 54 years; range, 20-92 years) counseled, 515 patients of non-AJ (all four grandparents) descent, diagnosed ≥age 50 years of age were genotyped, 55 with triple-negative BC (TNBC) and 460 with non-TNBC. One of the recurring PVs in BRCA1/BRCA2 were detected in 12.7% (7/55) of TNBC patients and 0.65% (3/460) of non-TNBC. One patient with non-TNBC had PMS2 PV. Low-penetrance variants were found in 2.5% of genotyped TNBC and in 3.7% of patients with non-TNBC, including CHEK2 c.499G>A (n = 3), APC c.3920T > A (n = 4), and heterozygous MUTYH c.1187G>A (n = 5). Following first-pass genotyping, 146 patients performed multigene panel testing, none carried a BRCA1/BRCA2 PV, and only 5/127 non-TNBC (3.9%) harbored PVs in CHEK2 (n = 2, c.846+1G>C and c.592+3A>T), ATM c.103C>T (n = 2), and NBN c.966C>G (n = 1)., Conclusions: The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients., (© 2024 American Cancer Society.)

Introduction: Hereditary breast and ovarian cancer (HBOC) is predominantly accounted for by pathogenic variants (PVs) in BRCA1/BRCA2 genes. Population screening for recurring PVs in Ashkenazi Jews (AJ) was incorporated into the Israeli health basket in 2020, increasing the identification of BRCA carriers. Information on cancer risks for each PV in Israel is limited., Aims: To assess genotype phenotype correlations of recurring BRCA PVs in Israeli carriers., Methods: A retrospective cohort of 3,478 BRCA carriers followed-up in 12 medical centers, comprising the HBOC Consortium, formed the basis of the study. Data were collected using the electronic database, and analyzed by Chi square, t-tests and Kaplan-Meier survival analysis., Results: Overall, 2145 BRCA1, 1131 BRCA2, and 22 double heterozygote PV carriers were analyzed. BRCA1 carriers had more cases of cancer (53.1% vs. 44.8%, p<0.001), ovarian cancer (OC) (17.1% vs. 10.6%, p<0.001), younger age at breast cancer (BC) (45.4 ±11.6SD years vs. 49.1 ±11.1SD years, p<0.001) and OC diagnosis (52.8 ±10.1SD yrs. vs. 61±10.6SD yrs. p<0.001), and more family history of BC (64.5% vs. 59.0%, p<0.001) and OC (36.7% vs. 27.3%, p<0.001) compared with BRCA2 carriers. Carriers of BRCA15382insC had more BC and less OC than BRCA1185delAG: 46.4% vs. 38.6% and 12.9% vs. 17.6% (p<0.04), respectively., Conclusions: In our population, similar to others, BRCA1 carriers have higher cancer rates and earlier age at diagnosis compared with BRCA2 carriers. The two recurring BRCA1 PVs have different risks: 5382insC carriers had more BC; 185delAG carriers had more OC. Risk-reducing measures should be based on variant-specific cancer risk.

Background: There are limited data on whether primary diagnosis of meningioma may be associated with development of secondary primary cancer (SPC)., Methods: All meningioma cases (ICD-O-3 morphology codes 9530/0-9539/3) diagnosed in Jewish Israelis ≥ 20 years 1990 through 2015 registered in the Israel National Cancer Registry (INCR) were retrieved. All subsequent cancers occurring more than 6 months after meningioma diagnosis were identified. Risk of secondary cancer (SPC) was compared to cancer risk in the general population through the calculation of standardized incidence ratios (SIRs) and excess absolute risks (EARs). SIRs were stratified by type of second cancer, sex, and age group. Cox regression models were used to estimate hazard ratios of developing SPC., Results: Overall, 8044 meningioma cases were identified: mean age at diagnosis was 64.0 ± 14.1 years. Of these, 927 (11.5%) were diagnosed with SPC (SIR 1.6, 95% CI 1.5-1.7). SPC risk was elevated in men (SIR 1.6, 95% CI 1.5-1.9) and women (SIR 1.6, 95% CI 1.5-1.8) diagnosed with meningioma in univariable analyses. Cancers most commonly encountered in the studied population were breast (17.6%), colorectal (13.4%), lung (8.1%), prostate (5%), and bladder (4.6%) cancer. In multivariable analyses, 10+ year increment in age at meningioma diagnosis was significantly associated with higher risk for SPC in individuals diagnosed with meningioma between 20 and 64 years, with an inverse association in the older age group (65+ years)., Conclusions: Meningioma diagnosis is associated with an increased risk for developing secondary cancers. This risk should be discussed with patients treated for meningioma., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

Background: The rate of risk-reducing bilateral mastectomy (RRBM) among cancer-free Israeli female BRCA1/BRCA2 mutation carriers was reportedly 13% in 2010. Current RRBM rates in Israel and factors seemingly associated with opting for RRBM were reevaluated., Methods: Israeli female cancer-free BRCA1/BRCA2 mutation carriers, who were followed at the high-risk clinic at Sheba Medical Center between January 2011 and April 2020 were eligible. Univariate Cox regression and log-rank test were used to study the crude association between potential predictors and performance of RRBM., Results: Overall, 427 cancer-free BRCA1 (n = 218) or BRCA2 (n = 209) mutation carriers were included. Median age at genotyping was 33.6 years (interquartile range 26.8-41.8 years), median follow-up 4.4 years (range 0.1-7.6 years). Overall, 41/427 (9.6%) participants underwent RRBM, all of them within 5 years of genotyping. Being married (HR-2.57, p = 0.017) and having a first degree relative with breast cancer (BC) (HR-2.19, p = 0.017) were positively associated with RRBM, whereas any previous benign breast biopsy was negatively associated (HR-0.48, p = 0.029) with performing RRBM., Conclusions: RRBM is still infrequently elected by Israeli BRCA1/BRCA2 mutation carriers, with married women with one relative with BC who have not undergone previous breast biopsy more likely to opt for RRBM.

Background: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear., Methods: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018., Results: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals., Conclusions: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

Background: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved., Method: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count., Results: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age- and ethnicity-matched women (53% with breast cancer)., Conclusion: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers., (© 2018 American Cancer Society.)

Purpose: To define the mutational spectrum of several candidate gene mutations in Israeli male breast cancer cases., Methods: MBC 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., Results: Overall, 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., Conclusion: BRCA1, BRCA2 and CHEK2 germline mutations contribute to inherited predisposition to MBC in Israel.

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.

Premature ovarian failure and diminished ovarian reserve have been noted both in female BRCA1/BRCA2 mutation carriers and in carriers of the Fragile X syndrome FMR1 gene CGG repeat size premutation. Based on the observation that BRCA mutation carriers do not harbour long CGG repeats in the FMR1 gene, it was hypothesized that BRCA-associated premature ovarian failure is mediated via FMR1. To test this notion, we evaluated the distribution of constitutional FMR1 genotypes in 188 BRCA1/BRCA2 mutation-positive Jewish Ashkenazi women and 15 708 female, mostly Ashkenazi controls in Israel. BRCA1/BRCA2 mutation carriers displayed a unique distribution of FMR1 genotypes compared with controls (p = 0·018) with a prominence of the shorter CGG alleles (<26 repeats). There was no allele size distribution differences within BRCA carriers when comparing cancer free (n = 95) and breast cancer affected women (n = 93) (p = 0·43). In conclusion, BRCA mutation carriers exhibit a distinct CGG FMR1 repeat size pattern compared with the general population, but it is unlikely to account for the reported diminished ovarian reserve or act as a modifier breast cancer gene in BRCA mutation carriers.

Several breast cancer risk prediction models have been validated in ethnically diverse populations, but none in Israeli high-risk women. To validate the accuracy of the IBIS and BOADICEA risk prediction models in Israeli high-risk women, the 10-year and lifetime risk for developing breast cancer were calculated using both BOADICEA and IBIS models for high-risk, cancer-free women, counselled at the Sheba Medical Center from 1 June 1996-31 May 2000. Women diagnosed with breast cancer by 31 May 2011 were identified from the Israeli National Cancer Registry. The observed to expected breast cancer ratios were calculated to evaluate the predictive value of both algorithms. Overall, 358 mostly (N = 205, 57·2%) Ashkenazi women, were eligible, age range at counselling was 20-75 years (mean 46·76 ± 9·8 years). Over 13·6 ± 1·45 years (range 11-16 years), 15 women (4·19%) were diagnosed with breast cancer, at a mean age of 57 ± 8·6 years. The 10-year risks assigned by BOADICEA and IBIS ranged from 0·2 to 12·6% and 0·89 to 21·7%, respectively. The observed:expected breast cancer ratio was 15/18·6 (0·8-95% CI 0·48-1·33) and 15/28·6 (0·52-95% CI 0·32-0·87), using both models, respectively. In Jewish Israeli high-risk women the BOADICEA model has a better predictive value and accuracy in determining 10-year breast cancer risk than the IBIS model.

Objective: To evaluate whether the presence or duration of uterine bleeding is associated with disease stage, and survival of patients with endometrioid endometrial carcinoma (EEC)., Methods: The records of 220 patients with EEC who underwent surgery were reviewed. The patients were divided into three groups according to the presence and duration of vaginal bleeding at the time of surgery. Group 1, without vaginal bleeding; group 2, vaginal bleeding up to 3 months; group 3, vaginal bleeding exceeding 3 months prior to surgery. Disease stage and survival were between the three groups., Results: Of the 220 patients, 42 (19%) were asymptomatic; 95 (43%) had symptom duration of up to 3 months and 83 (38%) experienced bleeding for >3 months. There were no significant differences between groups 1, 2 and 3 regarding the proportion of patients with deep invasion in stage I (21, 24, 26%, p = 0.84; respectively), with grade 3 tumors (10, 13, 14%, p = 0.42; respectively) or with advanced stage disease (12, 14, 15%, p = 0.92; respectively). Survival analysis demonstrated a non-significant trend toward better survival in asymptomatic patients and in patients with a shorter duration of symptoms (p = 0.172)., Conclusions: Diagnosis of EEC in asymptomatic patients or in patients with a short duration of bleeding is associated with comparable stage and survival.

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.

The genetic basis for gastric and pancreatic cancer is largely undetermined. These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes. Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984&#95;3987dupGTCA; c.3959&#95;3962delCAAG) genes can be detected. The MSH6*c.3984&#95;3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer. To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143-70%) were Ashkenazi Jews, and 10% (n = 16)--of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96-67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984&#95;3987dupGTCA and c.3959&#95;3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations. We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients.

BRCA1 and BRCA2 mutation carriers have an increased risk for developing breast (and ovarian) cancer. Non-carriers from within such families (=true negatives) are counseled that their risk for developing breast cancer is similar to that of the average-risk population. Breast cancer diagnosed in a non-carrier from a family with a known mutation is coined phenocopy. The rate of breast cancer phenocopy and the risk for breast cancer in true negatives are unsettled. The rate of phenocopy breast cancer was assessed in non-carriers from Jewish families with a BRCA1 or BRCA2 mutation, identified at the Sheba medical center. Analysis was performed by t test for comparison of mean age at counseling or breast cancer diagnosis, and by calculating a standardized incidence ratio (SIR). Overall, 1318 females from 884 mutation carrying families (620 with BRCA1 264 with BRCA2 mutations) were genotyped, of whom 307 women from 245 families were assigned a true negative status (mean age at counseling 43.01 ± 13.03 years (range 19.7-92.8 years). Of these true negatives, 20 women (6.51-2.26% of families) developed breast cancer at a mean age of 54.1 ± 12.9 years (range 48.1 -60.1 years). The SIR for breast cancer in true negatives was not significantly different than the expected in the average-risk Israeli population [observed 20-expected 23.8 cases SIR = 0.84, 95% CI (0.51, 1.30)]. The rate of phenocopy breast cancer in non-carriers from Israeli BRCA1 BRCA2 mutation carrier families is 2.26% with no increased breast cancer risk over the average-risk population.

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n = 638) or BRCA2 (n = 250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65 ± 12.2 years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8 ± 10.8 years) and the rest (n = 373-42%) were asymptomatic carriers (age at counseling 40.7 ± 10.6 years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5 years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR = 1.84 95% CI 1.465-2.314, P = 0.001) and paternal compared with maternal origin of mutation (OR = 1.55 95% CI 1.14-2.12, P = 0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.

Three mutations in BRCA1 (185delAG, 5382InsC) and BRCA2 (6174delT) predominate among high risk breast ovarian cancer Ashkenazi Jewish families, with few "private" mutations described. Additionally, the spectrum of BRCA1 and BRCA2 germline mutations among high risk Jewish non Ashkenazi and non Jewish Israelis is undetermined. Genotyping by exon-specific sequencing or heteroduplex analysis using enhanced mismatch mutation analysis was applied to 250 high risk, predominantly cancer affected, unrelated Israeli women of Ashkenazi (n = 72), non Ashkenazi (n = 90), Moslem (n = 45), Christian Arabs (n = 21), Druze (n = 17), and non Jewish Caucasians (n = 5). All Jewish women were prescreened and did not harbor any of the predominant BRCA1 or BRCA2 Jewish mutations. Age at diagnosis of breast cancer (median ± SD) (n = 219) was 40.1 ± 11.7, 45.6 ± 10.7, 38.7 ± 9.2, 45.5 ± 11.4 ± and 40.7 ± 8.1 years for Ashkenazi, non Ashkenazi, Moslem, Christian, and Druze participants, respectively. For ovarian cancer (n = 19) the mean ages were 45.75 ± 8.2, 57.9 ± 10.1, 54 ± 8, 70 ± 0, and 72 ± 0 for these origins, respectively. Overall, 22 (8.8%) participants carried 19 clearly pathogenic mutations-10 BRCA1 and 9 BRCA2 (3 novel): 3 in Ashkenazim, 6 in 8 non-Ashkenazim, 6 in 7 Moslems, 2 in Druze, and 2 in non Jewish Caucasians. Only three mutations (c.1991del4, C61G, A1708E) were detected in 2 seemingly unrelated families of Moslem and non- Ashkenazi origins. There were no inactivating mutations among 55 Ashkenazi high risk breast cancer only families. In conclusion, there are no predominant recurring germline mutations in BRCA1 or BRCA2 genes among ethnically diverse Jewish and non Jewish high risk families in Israel.

Recurring mutations in the BRCA1 gene are noted in some populations and represent either founder mutations or a mutational hot spot. The C61G*BRCA1 (c.181T>G) missense mutation is a pathogenic one commonly reported in Polish individuals. A Jewish non-Ashkenazi family (of Italian ancestry) was found to carry this mutation, and the present study aimed at evaluating whether this mutation represents a founder mutation or a mutational hot spot. To that end, multilocus allelotyping using five markers intragenic to and flanking the BRCA1 gene spanning a genomic region of approximately 1.5 Mbp was carried out in that family and in 20 unrelated Polish C61G*BRCA1 mutation carriers. Phasing was done using affected and unaffected Jewish family members. The alleles that compose the pathogenic, mutation-carrying intragenic BRCA1 haplotype of the Jewish mutation carriers were detected in 18/20 Polish mutation carriers. The two flanking markers farthest away showed more diversity, between and even within Polish individuals. In conclusion, the *BRCA1 missense mutation is a founder mutation that can be detected in geographically related populations.

To evaluate the contribution of MC1R variants to malignant melanoma risk in Israeli Jews, sequencing of the MC1R gene was performed in 132 melanoma patients and 184 ethnically matched controls. Overall, 22 MC1R variants were detected, two were novel (M73I and 496&#95;497insG). Using age and sex-adjusted logistic regression, one specific variant, R151C, conferred significantly increased melanoma risk among Ashkenazim (OR=2.6, 95% CI: 1.3-5.3; p=0.05 after Bonferroni correction). A gene dosage effect was noted, with significantly increased melanoma risk being observed in subjects with at least two variants whether when all variants are pooled (OR=4.8, 95% CI: 2.0-11.2; p=0.002 after Bonferroni correction) or when red hair colour (RHC) variants and non-RHC variants are distinguished (OR=7.6, 95% CI: 2.8-20.3; p=0.0004 after Bonferroni correction). If further studies support these findings, the assessment of MC1R status may be useful in identifying Jewish Israeli individuals at high risk for melanoma.

Background: A single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive., Objective: To evaluate the rate of the G2019S(*) LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls., Patients and Methods: Overall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test., Results: Overall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 +/- 10.9 years compared with an age at diagnosis of 61.1 +/- 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls)., Conclusion: The G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 x 10(-6)), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly MLH1, MSH2, and MSH6, underlie Hereditary non-polyposis colorectal cancer (HNPCC) and are mostly family-specific, with few reported founder mutations in MSH2 (Ashkenazim) MLH1 (Finnish). No mutations in colon cancer susceptibility genes have ever been reported in Druze individuals, a Moslem related faith encompassing approximately 1,000,000 individuals worldwide. A novel MSH2 mutation is described in a Druze HNPCC family: a multigenerational family with 10 members in 4 generations affected with colorectal cancer (mean age of diagnosis 46.5 years), two with gastric cancer and one--endometrial cancer. Mutational analysis of the MSH2 gene using denaturing gradient gel electrophoresis (DGGE) and direct sequencing revealed the c.702delA mutation in codon 234 of exon 4 of the MSH2 gene leading to a premature early stop in codon 245, p.Thr234fsX245. Analysis of mutation-carrying or presumed carriers individuals' offspring, revealed 11/42 asymptomatic mutation carriers, age range 17-50 years. The mutation was not present in two additional Druze HNPCC families and 20 Druze sporadic colon cancer patients. This is the first mutation ever reported in a colon cancer susceptibility gene in a Druze family and it appears not to be a founder mutation in Druze individuals with HNPCC.

Background: Germline mutations in BRCA1 and BRCA2 genes account for only 20-40% of familial breast cancer cases. The CHEK2 gene encodes a checkpoint kinase, involved in response to DNA damage, and hence is a candidate gene for breast cancer susceptibility. Indeed, the CHEK2*1100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK2*1100delC variant in the Ashkenazi Jewish population was reported to be 0.3%., Objectives: To evaluate whether CHEK2 germline mutations contribute to a breast cancer predisposition in Ashkenazi** Jewish high risk families., Methods: High risk Ashkenazi Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were genotyped for germline mutations in the CHEK2 gene by exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis and sequencing of abnormally migrating fragments., Results: Overall, 172 high risk women were genotyped: 75 (43.6%) with breast cancer (average age at diagnosis 49.6 +/- 9.6 years, mean +/- SD) and 97 asymptomatic individuals (age at counseling 48.3 +/- 8.2 years). No truncating mutations were noted and four previously described missense mutations were detected (R3W 1.2%, 1157T 1.2%, R180C 0.6% and S428F 5%), one silent polymorphism (E84E 20.5%) and one novel missense mutation (Y424H 1.2%). Segregation analysis of the 1157T and S428F mutations (shown to affect protein function) with the cancer phenotype showed concordance for the CHK2*1157T mutation, as did two of three families with the CHK2*S428F mutation., Conclusions: CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.