1,275 research outputs found
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Is schizophrenia a risk factor for breast cancer? â Evidence from genetic data
Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40,675 cases and 64,643 controls) and breast cancer (n = 122,977 cases and 105,974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship.
Using LD-score regression, we found that there is a small but significant genetic correlation between the two disorders (rG = 0.14, S.E = 0.03, p = 4.75 x 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (S.E. = 0.009, p = 2.3 x 10-4). A one standard deviation increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, S.E. = 0.012, p =0.67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results.
These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship
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PHIP â a novel candidate breast cancer susceptibility locus on 6q14.1
Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.The study was supported by grants provided by the Swedish Cancer Society (Cancerfonden), the Stockholm County Council (ALF project), the Swedish Research Council (VetenskapsrĂ„det), the Stockholm Cancer Society (Radiumhemsfonderna) and Bert von Kantzows and Nilsson-Ehleâs foundations. BCAC is funded by Cancer Research UK (C1287/A16563, C1287/A10118), the European Unionâs Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and by the European CommunityÂŽs Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Funding for the iCOGS infrastructure came from: the European Communityâs Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. Funding of individual BCAC studies is listed in the Supplemental Note
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Oral contraceptive use and breast cancer risk: retrospective and prospective analyses from a BRCA1 and BRCA2 mutation carrier cohort study
Background
For BRCA1 and BRCA2 mutation carriers, the association between oral contraceptive preparation (OCP) use and breast cancer (BC) risk is still unclear.
Methods
BC risk associations were estimated from OCP data on 6,030 BRCA1 and 3,809 BRCA2 mutation carriers using age-dependent Cox regression, stratified by study and birth cohort. Prospective, left-truncated retrospective and full-cohort retrospective analyses were performed.
Results
For BRCA1 mutation carriers, OCP use was not associated with BC risk from prospective analyses (Hazard Ratio (HR) 1.08;95% Confidence Interval (CI) 0.75-1.56), but from the left-truncated and full-cohort retrospective analyses risks were increased by 26% (95%CI 6%-51%) and 39% (95%CI 23%-58%), respectively. For BRCA2 mutation carriers, OCP use was associated with BC risk from prospective analyses (HR 1.75;95%CI 1.03-2.97), but retrospective analyses were inconsistent (left-truncated: HR 1.06;95%CI 0.85-1.33; full-cohort: HR 1.52;95%CI 1.28-1.81). There was evidence of increasing risk with duration of use, especially before first full-term pregnancy (BRCA1: both retrospective analyses, p<0.001 and p=0.001, respectively; BRCA2: full-retrospective analysis, p=0.002).
Conclusions
Prospective analyses did not show that past use of OCP is associated with an increased BC risk for BRCA1 mutation carriers in young middle age women (40-50 years). For BRCA2 mutation carriers, a causal association is also not likely at those ages. Findings between retrospective and prospective analyses were inconsistent and could be due to survival bias or a true association for younger women who were underrepresented in the prospective cohort. Given uncertain safety of OCP use for BRCA1/2 mutation carriers, indications other than contraception should be avoided and non-hormonal contraceptive methods discussed
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Identification of nine new susceptibility loci for endometrial cancer
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS) we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5,624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes and risk alleles at two of these loci that associate with decreased expression of genes which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study
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Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study
Background: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization analysis comprising 15,748 breast and 22,898 prostate cancer cases. Demonstrating causality has proven challenging, and one common limitation of MR studies is insufficient power.
Methods: We aim to determine if circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary level data from the largest-ever genome-wide association studies conducted on vitamin D (N=73,699), breast cancer (Ncase=122,977) and prostate cancer (Ncase=79,148). We constructed a stronger instrument using six common genetic variants (as compared with the previous four variants), and applied several two-sample MR methods.This work was supported by the VeteskapsrÄdet International Postdoc grant (XJ), the World Cancer Research Fund International Regular Grant Programme (WCRF 2014/1180) (KKT), the World Cancer Research Fund International grant (WCRF 2015/1421) (SL), the National Cancer Institute Grant (R00 CA207848) (SWA), the Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (C18281/A19169) (RMM), and the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol
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Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWASs) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P<5x10 with 10 variants at nine novel loci. At P< 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative or BRCA1 mutation carrier GWASs, and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other breast cancer GWASs. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 carriers. These findings will likely lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.Genotyping for the OncoArray was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the MinistĂšre de l'Ăconomie, de la Science et de l'Innovation du QuĂ©bec through GĂ©nome QuĂ©bec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer ControlâMinistry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837).
Genotyping for the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the MinistĂšre de l'Ăconomie, Innovation et Exportation du QuĂ©bec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund.
Combination of the GWAS data was supported in part by the NIH Cancer Post-Cancer GWAS initiative (1 U19 CA 148065) (DRIVE, part of the GAME-ON initiative). LD score regression analysis was supported by grant CA194393.
BCAC is funded by Cancer Research UK (C1287/A16563) and by the European Union via its Seventh Framework Programme (HEALTH-F2-2009-223175, COGS) and the Horizon 2020 Research and Innovation Programme (633784, B-CAST; 634935, BRIDGES). CIMBA is funded by Cancer Research UK (C12292/A20861 and C12292/A11174)
A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes
In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene âBRCA3â, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021â0.125%) and of BRCA2 0.068% (95% CI: 0.033â0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families
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