Efrat Dagan

A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5′ untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P = 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6–9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3–9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.

Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women.

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, hyperhomocysteinaemia and increased risk for atherosclerosis in homozygotes. We examined the frequency of this mutation and its association with disease pattern in 491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n = 136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2 mutation carriers, genotyped for the three predominant Jewish founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes were equally distributed among women with sporadic breast and/or ovarian cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205; 21.0%) (P=non-significant). 677T homozygotes were equally distributed among women diagnosed with breast cancer prior to (22/122; 18.0%) and after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes in manifesting cancer (32/136; 23.5%) and asymptomatic individuals (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among women with bilateral breast cancer and those with both breast and ovarian carcinoma than among those with unilateral breast cancer (64/365; 17.5%). Differences in morbidity (one versus multiple breast/ovarian tumours) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations. Confirmation of these data, namely, that the 677T allele is significantly more common in cases of bilateral breast cancer or combined breast and ovarian cancer would have important clinical implications.

Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers

Background:The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes.Methods:Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed.Results:Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33–83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10–23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6–15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039).Conclusion:Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Mutational analyses of BRCA1 and BRCA2 in Ashkenazi and non-Ashkenazi Jewish women with familial breast and ovarian cancer.

In Ashkenazi (East European) Jews, three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) account for the majority of germline mutations in high‐risk breast and/or ovarian cancer families. Among non‐Ashkenazi Jews, the 185delAG, Tyr978Ter, and a handful of “private” mutations have been reported anecdotally within both genes. In this study we attempted to determine the spectrum of BRCA1 and BRCA2 mutations in high‐risk Jewish individuals, non‐carriers of any of the predominant Jewish mutations. We employed multiplex PCR and denaturing gradient gel electrophoresis (DGGE) analysis for BRCA2, and combined denaturing high performance liquid chromatography (DHPLC) and protein truncation test (PTT) for BRCA1, complemented by DNA sequencing. We screened 47 high‐risk Jewish individuals, 26 Ashkenazis, and 21 non‐Ashkenazis. Overall, 13 sequence alterations in BRCA1 and eight in BRCA2 were detected: nine neutral polymorphisms and 12 missense mutations, including five novel ones. The novel missense mutations did not co‐segregate with disease in BRCA1 and were detected at rates of 6.25% to 52.5% in the general population for BRCA2. Our findings suggest that except for the predominant mutations in BRCA1 and BRCA2 in Jewish individuals, there are only a handful of pathogenic mutations within these genes. It may imply novel genes may underlie inherited susceptibility to breast/ovarian cancer in Jewish individuals. Hum Mutat 16:491–501, 2000.

Androgen receptor CAG repeat length in Jewish Israeli women who are BRCA1/2 mutation carriers: association with breast/ovarian cancer phenotype

BRCA1/2 mutation carriers are at an increased risk for developing breast and/or ovarian cancer. Yet, the genetic and environmental factors that govern the phenotypic expression of mutant BRCA1/2 alleles remain elusive. The CAG repeat within exon 1 of the androgen receptor (AR) gene is reportedly associated with breast cancer phenotype in BRCA1 mutation carriers. Two hundred and twenty seven BRCA1/2 mutation carriers were genotyped for the polymorphic AR CAG repeat, and allele size was correlated with breast/ovarian cancer morbidity parameters. Of 227 BRCA1/2 carriers, 169 were BRCA1 mutation carriers and 58 carried a BRCA2 mutation, 149 had breast and/or ovarian cancer and 78 were asymptomatic mutation carriers. The mean age at diagnosis in women with either or both neoplasms was 46.7±11.2 years, and that of the asymptomatic group – 45.8±9.4 years, a statistically insignificant difference. The AR CAG repeat ranged from eight to 28 in all tested women, and the mean number of the repeats were not statistically different between affected (18.3±2.4) and asymptomatic mutation carriers (18.6±2.1). The AR CAG repeat among patients with early onset (<42 years) breast cancer was significantly shorter (17.5±2.3) compared with asymptomatic individuals (18.6±2.1) (P<0.01), and the shorter allele – the younger the age at diagnosis. There is no conclusive evidence of association between AR CAG repeat size and breast or ovarian cancer risk in Jewish BRCA1/2 mutation carriers. A small effect of a short AR CAG allele size on breast cancer at early age (<42 years) cannot be excluded.

Impact of pregnancy and lactation on GABAA receptor and central-type and peripheral-type benzodiazepine receptors

The effect of pregnancy and lactation on GABA(A) receptor and central- and peripheral-type benzodiazepine receptors (CBR and PBR, respectively) was studied in female Sprague-Dawley rats. Pregnancy was associated with increased CBR density (on day 19) in the hippocampus and with decreased [3H]Ro 15-1788-specific binding in the hypothalamus during pregnancy and lactation. A similar decrease in [3H]PK 11195-specific binding was observed in the hypothalamus and pituitary. An increase in PBR density in the ovary and uterus was observed during pregnancy, while adrenal PBR density was down-regulated during pregnancy and lactation. It seems that the hormonal changes occurring during pregnancy and lactation play a role in the regulation of CBR and PBR in discrete tissues.

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder caused by mutations in the autophagy gene EPG5. Byrne et al. characterise the phenotype of 50 affected children, revealing callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, immune dysfunction, developmental delay and microcephaly. Downregulation of epg5 in Drosophila results in autophagic abnormalities and progressive neurodegeneration.

The twilight zone between health and sickness: a qualitative exploration with asymptomatic BRCA1 and 2 mutation carriers.

Purpose. To explore the way in which asymptomatic women diagnosed with mutation in BRCA1 or BRCA2 genes give meaning to their family scripts and to the dialectic between being concurrently healthy and at high risk for breast and ovarian cancer, vis-à-vis their way of coping with risks. Methods. Seventeen asymptomatic Israeli women diagnosed as BRCA1 or 2 mutation carriers participated in the study. In-depth semi-structured interviews were conducted. Data were analyzed using qualitative-phenomenological methods. Results. The following themes were revealed: (1) Cancer or surgery: the dominant fear; (2) Family clock; (3) Knowledge is power, and (4) Mothers story shapes daughters construction of experience. Conclusion. Breast and ovarian cancer worry was a major factor in opting for prophylactic oophorectomy. Family scripts, the hope to be healthy and the wish to live through significant stages in family life may lead to the choice of prophylactic oophorectomy among asymptomatic BRCA1 or 2 mutation carriers. However, it does not propel these women to opt for bilateral prophylactic mastectomy. Listening to different voices regarding risk reduction modalities is crucial among genetic counselors and health providers for health promotion in women at high risk.

The contribution of Niemann-Pick SMPD1 mutations to Parkinson disease in Ashkenazi Jews

INTRODUCTION Parkinson disease is noted for its association with mutations in GBA and the p.G2019S mutation in LRRK2. This study aimed to evaluate the frequency of Ashkenazi founder mutations in sphingomyelin phosphodiesterase 1 (SMPD1) in Ashkenazi patients diagnosed with Parkinsons disease (PD); and their impact on PD phenotypic expression. SMPD1 underlies the lysosomal storage disease - Niemann-Pick. METHODS A case (n = 287) control (n = 400) study was undertaken. All patients underwent a physical, neurobehavioral and neurologic examination that incorporated the Unified Parkinsons Disease Rating Scale. Three founder SMPD1 Ashkenazi mutations (c.996delC (fsP330), p.L302P and p.R496L) were investigated in patients and controls, previously evaluated for carriage of founder mutations in GBA and the p.G2019S mutation in LRRK2. RESULTS Nine (3.1%) PD patients compared to two (0.5%) individuals from the control group were found to carry one of the three Ashkenazi SMPD1 founder mutations (p = 0.007). The overall clinical characteristics of PD patients carrying SMPD1 mutations were similar to those of PD patients with no mutations in SMPD1, GBA and LRRK2 (n = 189). CONCLUSION We maintain that disruptive mutations in SMPD1 constitute a risk factor for PD.

Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer.

To delineate the clinical, genetic and family history attributes in Jewish Ashkenazi women with early onset (< 42 years) breast cancer we genotyped such women for the three predominant Jewish Ashkenazi mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT). The study cohort was composed of 172 women diagnosed with breast cancer at or before the age of 42 years, obtained from the oncology department registry. Mutations were identified in 54 women (31%). Of 79 women with a positive family history for breast and/or ovarian cancer, and 93 with no such family history, 45 (57%) and 9 (10%), respectively, were mutation carriers (chi2 = 46; P < 0.001). Contralateral breast cancer occurred in 15 of 54 mutation carriers (28%) compared with 8 of 118 (7%) non-carriers (chi2= 14; P < 0.001). Early onset breast cancer per se is a weak predictor of finding germ line mutation(s) in BRCA1 and BRCA2, unless associated with a positive family history and/or bilaterality.