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BRCA1 polymorphisms and breast cancer epidemiology in the Western New York exposures and breast cancer (WEB) study.

ABSTRACT: Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case-control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case-control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional, polytomous logistic regression and ?(2) -tests were used to examine the associations of breast cancer with genotypes and haplotypes. In addition, interactions between genotype and smoking, benign breast disease, family history of breast cancer, body mass index (BMI), alcohol consumption, and hormonal risk factors, hormone receptor status, and breast cancer pathology were calculated also using logistic regression and ?(2) . Although sporadic breast cancer was not associated with BRCA1 genotypes or haplotypes overall or by menopausal status, there was evidence of an interaction between the E1038G BRCA1 genotype, smoking, and BMI among premenopausal women (P for interaction = 0.01 and 0.045, respectively) and between E1038G and D693N BRCA1 genotypes and hormone therapy use among postmenopausal women (P for interaction = 0.01 and 0.02, respectively). There were no other associations found between BRCA1 genotypes and stage, histological grade, or nuclear grade. However, the D693N SNP was associated with the risk of triple negative breast cancer (odds ratio = 2.31 95% confidence interval 1.08-4.93). The BRCA1 variants studied may play a role in the etiology of triple negative breast cancer and may interact with environmental factors such as hormone therapy or smoking and increase sporadic breast cancer risk.

SUBMITTER: Ricks-Santi LJ

PROVIDER: S-EPMC3699175 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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BRCA1 polymorphisms and breast cancer epidemiology in the Western New York exposures and breast cancer (WEB) study.

Ricks-Santi Luisel J LJ Nie Jing J Marian Catalin C Ochs-Balcom Heather M HM Trevisan Maurizio M Edge Stephen B SB Kanaan Yasmine Y Freudenheim Jo L JL Shields Peter G PG

Genetic epidemiology 20130514 5

Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case-control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case-control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional ...[more]

PMID: 23674270

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Project description:BACKGROUND: BRCA1 and BRCA2 germline mutations predispose heterozygous carriers to hereditary breast/ovarian cancer. However, unclassified variants (UVs) (variants with unknown clinical significance) and missense polymorphisms in BRCA1 and BRCA2 genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is still unclear. The objective of our study was to identify UVs and missense polymorphisms in Algerian breast/ovarian cancer patients and relatives tested previously for BRCA1 and BRCA2 genes germline mutations analysis. METHODS: We analyzed 101 DNA samples from 79 breast/ovarian cancer families. The approach used is based on BRCA1 and BRCA2 sequence variants screening by SSCP or High-Resolution Melting (HRM) curve analysis followed by direct sequencing. In silico analyses have been performed using different bioinformatics programs to individualize genetics variations that can disrupt the BRCA1 and BRCA2 genes function. RESULTS: Among 80 UVs and polymorphisms detected in BRCA1/2 genes (33 BRCA1 and 47 BRCA2), 31 were new UVs (10 BRCA1 and 21 BRCA2), 7 were rare UVs (4 BRCA1 and 3 BRCA2) and 42 were polymorphic variants (19 BRCA1 and 23 BRCA2). Moreover, 8 new missense UVs identified in this study: two BRCA1 (c.4066C>A/p.Gln1356Lys, c.4901G>T/p.Arg1634Met) located respectively in exons 11 and 16, and six BRCA2 (c.1099G>A/p.Asp367Asn, c.2636C>A/p.Ser879Tyr, c.3868T>A/p.Cys1290Ser, c.5428G>T/p.Val1810Phe, c.6346C>G/p.His2116Asp and c.9256G>A/p.Gly3086Arg) located respectively in exons 10, 11 and 24, show a damaging PSIC score yielded by PolyPhen2 program and could be pathogenic. In addition, 5 new BRCA} missense UVs out of six that were found to be damaging by PolyPhen2 program, also were deleterious according to SIFT program. The rare BRCA1 UV c.5332G>A/p.Asp1778Asn was found here for the first time in co-occurrence in trans with the deleterious BRCA1 mutation c.798_799delTT/p.Ser267LysfsX19 in young breast cancer patient. Moreover, 10 new identified intronic variants with unknown clinical significance (3 BRCA1 and 7 BRCA2) in the present study, could be considered as benign, because GeneSplicer, SpliceSiteFinder and MaxEntScan prediction programs show no splice site alteration for these variants. Several missense polymorphisms of BRCA1 c.2612C>T/p.Pro871Leu, c.3548A>G/p.Lys1183Arg, c.4837A>G/p.Ser1613Gly and BRCA2 c.865A>C/p.Asn289His, c.1114A>C/p.Asn372His, c.2971A>G/p.Asn991Asp, c.7150C>A/p.Gly2384Lys have been identified with high frequency in patients who were tested negative for BRCA1 and BRCA2 mutations. These missense polymorphisms could have a role as susceptibility breast cancer markers in Algerian breast/ovarian cancer families where pathological BRCA1 and BRCA2 mutations were not present. CONCLUSIONS: For the first time, UVs and missense polymorphisms in BRCA1 and BRCA2 genes have been identified in Algerian breast/ovarian cancer families. Evaluation of breast/ovarian cancer risk induced by the eight new missense UVs and common polymorphisms detected in our present work is on going in a larger study.

Project description:BackgroundExperimental animal studies and limited epidemiologic evidence suggest that prenatal exposure to phthalates may be obesogenic, with potential sex-specific effects of phthalates having anti-androgenic activity.ObjectivesWe aimed to assess associations between prenatal phthalate exposures and childhood fat mass in a prospective cohort study.MethodsWe measured phthalate metabolite concentrations in third-trimester maternal urine in a cohort of women enrolled in New York City between 1998 and 2002 (n = 404). Among 180 children (82 girls and 98 boys), we evaluated body composition using a Tanita scale at multiple follow-up visits between ages 4 and 9 years (363 total visits). We estimated associations of standard deviation differences or tertiles of natural log phthalate metabolite concentrations with percent fat mass using linear mixed-effects regression models with random intercepts for repeated outcome measurements. We assessed associations in multiple metabolite models and adjusted for covariates including prepregnancy body mass index, gestational weight gain, maternal smoking during pregnancy, and breastfeeding.ResultsWe did not observe associations between maternal urinary phthalate concentrations and percent body fat in models examining continuous exposures. Fat mass was 3.06% (95% CI: -5.99, -0.09%) lower among children in the highest tertile of maternal urinary concentrations of summed di(2-ethylhexyl) phthalate (ΣDEHP) metabolites than in children in the lowest tertile. Though estimates were imprecise, there was little evidence that associations between maternal urinary phthalate concentrations and percent fat mass were modified by child's sex.ConclusionsPrenatal phthalate exposures were not associated with increased body fat among children 4-9 years of age, though high prenatal DEHP exposure may be associated with lower fat mass in childhood.CitationBuckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, Wolff MS, Herring AH. 2016. Prenatal phthalate exposures and childhood fat mass in a New York City cohort. Environ Health Perspect 124:507-513; http://dx.doi.org/10.1289/ehp.1509788.

Dataset Information

BRCA1 polymorphisms and breast cancer epidemiology in the Western New York exposures and breast cancer (WEB) study.

Publications

BRCA1 polymorphisms and breast cancer epidemiology in the Western New York exposures and breast cancer (WEB) study.

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