Similar Datasets
Project description:Identification of aberrant luminal progenitors and mTORC1 as a potential chemoprevention target in BRCA2 mutation carriers
| PRJNA976362 | ENA
Project description:PURPOSE:BRCA gene mutations and elevated serum estradiol (E(2)) are well-known risk factors for breast cancer. The aim of this study was to investigate the association between BRCA gene mutations and serum E(2) level. METHODS:We measured baseline (menstrual cycle day 2-3) E(2) levels of 96 women with breast cancer who underwent BRCA testing. RESULTS:The mean age, parity, and age at menarche did not differ between women with and without BRCA1/2 mutations. Basal serum E(2) level was significantly higher in women with BRCA2 mutations compared to women with BRCA1 mutations or without BRCA mutations (71.7 ± 41.6 vs. 45.5 ± 20.7 vs. 38.5 ± 12.6 pg/ml in BRCA2 mutation carriers, BRCA1 mutation carriers, and non-carriers, respectively, p value = 0.03). Women with BRCA2 mutations had 3.1 times as great risk for high basal E(2) level (>48 pg/ml) as women without BRCA mutations after adjusting for age and BMI (95 % confidence interval: 1.3, 7.6). BRCA mutation carriers with high serum E(2) level were significantly younger than the carriers with low serum E(2) level (31.4 ± 3.1 vs. 34.7 ± 4.9 years, p = 0.04). CONCLUSIONS:In this pilot study, we found an association between high basal serum E(2) levels and BRCA2 mutations. Our results suggest that increased production of E(2) may have a role in the pathogenesis of BRCA2-mutation-related breast cancer.
| S-EPMC3583585 | biostudies-literature
Project description:RNA-sequencing was performed on patient luminal progenitor breast cell subsets from premenopausal, preneoplastic BRCA2 mutation carriers and non-carriers to interrogate early transcriptional alterations in BRCA2mut/+ cells.
2023-12-12 | GSE233310 | GEO
Project description:RNA-sequencing was performed on patient luminal progenitor breast cell subsets from premenopausal, preneoplastic BRCA2 mutation carriers and non-carriers to interrogate early transcriptional alterations in BRCA2mut/+ cells.
2023-12-12 | GSE233309 | GEO
Project description:Cancer occurrence in 164 families with breast/ovarian cancer and germline BRCA2 mutations was studied to evaluate the evidence for genotype-phenotype correlations. Mutations in a central portion of the gene (the "ovarian cancer cluster region" [OCCR]) were associated with a significantly higher ratio of cases of ovarian:breast cancer in female carriers than were mutations 5' or 3' of this region (P<.0001), extending previous observations. The optimal definition of the OCCR, as judged on the basis of deviance statistics, was bounded by nucleotides 3059-4075 and 6503-6629. The relative and absolute risks of breast and ovarian cancer associated with OCCR and non-OCCR mutations were estimated by a conditional likelihood approach, conditioning on the set of mutations observed in the families. OCCR mutations were associated both with a highly significantly lower risk of breast cancer (relative risk [RR] 0.63; 95% confidence interval (95% CI) 0.46-0.84; P=.0012) and with a significantly higher risk of ovarian cancer (RR = 1.88; 95% CI = 1.08-3.33; P=.026). No other differences in breast or ovarian cancer risk, by mutation position, were apparent. There was some evidence for a lower risk of prostate cancer in carriers of an OCCR mutation (RR = 0.52; 95% CI = 0.24-1.00; P=.05), but there was no evidence of a difference in breast cancer risk in males. By age 80 years, the cumulative risk of breast cancer in male carriers of a BRCA2 mutation was estimated as 6.92% (95% CI = 1.20%-38.57%). Possible mechanisms for the variation in cancer risk are suggested by the coincidence of the OCCR with the RAD51-binding domain.
| S-EPMC1235274 | biostudies-literature
Project description:ObjectiveTo compare antimüllerian hormone (AMH) levels in women at high risk for hereditary breast and ovarian cancer compared with healthy low-risk control women.DesignProspective cohort.SettingNot applicable.Patient(s)Reproductive-age women with a uterus and both ovaries were analyzed in four groups: BRCA1 mutation carriers, BRCA2 carriers, BRCA-negative women, and low-risk controls.Intervention(s)Self-collected dried blood spot.Main outcome measure(s)AMH levels.Result(s)One hundred ninety-five women were included: 55 BRCA1 carriers, 50 BRCA2 carriers, 26 BRCA negative women, and 64 low-risk controls. After adjusting for confounders, BRCA2 carriers had AMH levels that were 33% lower than control women and an increased odds of having AMH <1 ng/mL. BRCA1 carriers and BRCA-negative women had AMH levels similar to control women. When analysis was restricted to regularly menstruating women younger than 40 years of age, BRCA2 carriers continued to demonstrate significantly lower AMH levels and increased likelihood of low AMH. Also, in this restricted group, BRCA-negative women demonstrated AMH levels that were 42% lower than control women. No difference in AMH was observed for BRCA1 carriers.Conclusion(s)We observed significantly lower AMH levels among BRCA2 carriers compared with low-risk control women. These results were stable across all models. BRCA-negative women also had lower AMH values, but only in models restricted to young regularly menstruating women. In contrast to earlier analyses, BRCA1 carriers had AMH values that were similar to low-risk control women, but this may be due to differences in the population studied.
| S-EPMC5531590 | biostudies-literature
Project description:BACKGROUND:The outcomes of sporadic pancreatic ductal adenocarcinoma (PDAC) patients with germline mutations of BRCA1/BRCA2 remains unclear. The prognostic significance of BRCA1/BRCA2 mutations on survival is not well established. STUDY DESIGN:We performed targeted next-generation sequencing (NGS) to identify BRCA1/BRCA2 germline mutations in resected sporadic PDAC cases from 2000 to 2015. Germline BRCA mutation carriers were matched by age and tumor location to those with BRCA1/BRCA2 wild-type genes from our institutional database. Demographics, clinicopathologic features, overall survival (OS), and disease-free survival (DFS) were abstracted from medical records and compared between the 2 cohorts. RESULTS:Twenty-two patients with sporadic cancer and BRCA1 (n = 4) or BRCA2 (n = 18) germline mutations and 105 wild-type patients were identified for this case-control study. The BRCA1/BRCA2 mutations were associated with inferior median OS (20.2 vs 27.8 months, p = 0.034) and DFS (8.4 vs 16.7 months, p < 0.001) when compared with the matched wild-type controls. On multivariable analyses, a BRCA1/BRCA2 mutation (hazard ratio [HR] 2.10, p < 0.001), positive margin status (HR 1.72, p = 0.021), and lack of adjuvant therapy (HR 2.38, p < 0.001), were all independently associated with worse survival. Within the BRCA1/BRCA2 mutated group, having had platinum-based adjuvant chemotherapy (n = 10) was associated with better survival than alternative chemotherapy (n = 8) or no adjuvant therapy (n = 4) (31.0 vs 17.8 vs 9.3 months, respectively, p < 0.001). CONCLUSIONS:Carriers of BRCA1/BRCA2 mutation with sporadic PDAC had a worse survival after pancreatectomy than their BRCA wild-type counterparts. However, platinum-based chemotherapy regimens were associated with markedly improved survival in patients with BRCA1/BRCA2 mutations, with survival differences no longer appreciated with wild-type patients.
| S-EPMC6178809 | biostudies-literature
Project description:Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
| S-EPMC3196382 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-02-01 | GSE32259 | GEO
Project description:INTRODUCTION:Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. METHODS:We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. RESULTS:We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP?, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). CONCLUSIONS:Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
| S-EPMC3446398 | biostudies-literature