Dataset Information

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

ABSTRACT: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR?=?0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

SUBMITTER: Gaudet MM

PROVIDER: S-EPMC3609647 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Gaudet Mia M MM Kuchenbaecker Karoline B KB Vijai Joseph J Klein Robert J RJ Kirchhoff Tomas T McGuffog Lesley L Barrowdale Daniel D Dunning Alison M AM Lee Andrew A Dennis Joe J Healey Sue S Dicks Ed E Soucy Penny P Sinilnikova Olga M OM Pankratz Vernon S VS Wang Xianshu X Eldridge Ronald C RC Tessier Daniel C DC Vincent Daniel D Bacot Francois F Hogervorst Frans B L FB Peock Susan S Stoppa-Lyonnet Dominique D Peterlongo Paolo P Schmutzler Rita K RK Nathanson Katherine L KL Piedmonte Marion M Singer Christian F CF Thomassen Mads M Hansen Thomas v O Tv Neuhausen Susan L SL Blanco Ignacio I Greene Mark H MH Garber Judith J Weitzel Jeffrey N JN Andrulis Irene L IL Goldgar David E DE D'Andrea Emma E Caldes Trinidad T Nevanlinna Heli H Osorio Ana A van Rensburg Elizabeth J EJ Arason Adalgeir A Rennert Gad G van den Ouweland Ans M W AM van der Hout Annemarie H AH Kets Carolien M CM Aalfs Cora M CM Wijnen Juul T JT Ausems Margreet G E M MG Frost Debra D Ellis Steve S Fineberg Elena E Platte Radka R Evans D Gareth DG Jacobs Chris C Adlard Julian J Tischkowitz Marc M Porteous Mary E ME Damiola Francesca F Golmard Lisa L Barjhoux Laure L Longy Michel M Belotti Muriel M Ferrer Sandra Fert SF Mazoyer Sylvie S Spurdle Amanda B AB Manoukian Siranoush S Barile Monica M Genuardi Maurizio M Arnold Norbert N Meindl Alfons A Sutter Christian C Wappenschmidt Barbara B Domchek Susan M SM Pfeiler Georg G Friedman Eitan E Jensen Uffe Birk UB Robson Mark M Shah Sohela S Lazaro Conxi C Mai Phuong L PL Benitez Javier J Southey Melissa C MC Schmidt Marjanka K MK Fasching Peter A PA Peto Julian J Humphreys Manjeet K MK Wang Qin Q Michailidou Kyriaki K Sawyer Elinor J EJ Burwinkel Barbara B Guénel Pascal P Bojesen Stig E SE Milne Roger L RL Brenner Hermann H Lochmann Magdalena M Aittomäki Kristiina K Dörk Thilo T Margolin Sara S Mannermaa Arto A Lambrechts Diether D Chang-Claude Jenny J Radice Paolo P Giles Graham G GG Haiman Christopher A CA Winqvist Robert R Devillee Peter P García-Closas Montserrat M Schoof Nils N Hooning Maartje J MJ Cox Angela A Pharoah Paul D P PD Jakubowska Anna A Orr Nick N González-Neira Anna A Pita Guillermo G Alonso M Rosario MR Hall Per P Couch Fergus J FJ Simard Jacques J Altshuler David D Easton Douglas F DF Chenevix-Trench Georgia G Antoniou Antonis C AC Offit Kenneth K

PLoS genetics 20130327 3

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were select ...[more]

PMID: 23544012

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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 analysed 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 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, 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 HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: 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. Total gene expression of normal breast sample from healthy controls. This submission represents transcriptome component of study.

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 analysed 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 2754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterised three cis-regulatory SNPs located at the promoter and two intronic regulatory elements, which affect the binding of the transcription factors C/EBPα, HMGA1, 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 HR=0.85, 95%CI=0.72-1.00, P-trend=0.048). Conclusion: 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. Genotype of normal breast sample from healthy controls.

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.

Dataset Information

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Publications

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

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