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Montserrat Garcia-Closas,
Fergus J Couch,
Sara Lindstrom,
Kyriaki Michailidou,
Marjanka K Schmidt,
Mark N Brook,
Nick Orr,
Suhn Kyong Rhie,
Elio Riboli,
Heather S Feigelson, [......],
Alison M Dunning,
Mark E Sherman,
Georgia Chenevix-Trench,
Stephen J Chanock,
Per Hall,
Paul D P Pharoah,
Celine Vachon,
Douglas F Easton,
Christopher A Haiman,
Peter Kraft
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ABSTRACT: Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
Nature Genetics 03/2013; 45(4):392-398. · 35.53 Impact Factor
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Kyriaki Michailidou,
Per Hall,
Anna Gonzalez-Neira,
Maya Ghoussaini, Joe Dennis,
Roger L Milne,
Marjanka K Schmidt,
Jenny Chang-Claude,
Stig E Bojesen,
Manjeet K Bolla, [......],
Sandra Deming-Halverson,
Martha Shrubsole,
Jirong Long,
Jacques Simard,
Montse Garcia-Closas,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Alison M Dunning,
Javier Benitez,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
Nature Genetics 03/2013; 45(4):353-361. · 35.53 Impact Factor
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Stig E Bojesen,
Karen A Pooley,
Sharon E Johnatty,
Jonathan Beesley,
Kyriaki Michailidou,
Jonathan P Tyrer,
Stacey L Edwards,
Hilda A Pickett,
Howard C Shen,
Chanel E Smart, [......],
Simon A Gayther,
Paul D P Pharoah,
Roger R Reddel,
Ellen L Goode,
Mark H Greene,
Douglas F Easton,
Andrew Berchuck,
Antonis C Antoniou,
Georgia Chenevix-Trench,
Alison M Dunning
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ABSTRACT: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Nature Genetics 03/2013; 45(4):371-384. · 35.53 Impact Factor
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Juliet D French,
Maya Ghoussaini,
Stacey L Edwards,
Kerstin B Meyer,
Kyriaki Michailidou,
Shahana Ahmed,
Sofia Khan,
Mel J Maranian,
Martin O'Reilly,
Kristine M Hillman, [......],
Anthony Swerdlow,
Alan Ashworth,
Nick Orr,
Minouk J Schoemaker,
Bruce A J Ponder,
Heli Nevanlinna,
Melissa A Brown,
Georgia Chenevix-Trench,
Douglas F Easton,
Alison M Dunning
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ABSTRACT: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
The American Journal of Human Genetics 03/2013; · 10.60 Impact Factor
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Mia M Gaudet,
Karoline B Kuchenbaecker,
Joseph Vijai,
Robert J Klein,
Tomas Kirchhoff,
Lesley McGuffog,
Daniel Barrowdale,
Alison M Dunning,
Andrew Lee, Joe Dennis, [......],
Guillermo Pita,
M Rosario Alonso,
Per Hall,
Fergus J Couch,
Jacques Simard,
David Altshuler,
Douglas F Easton,
Georgia Chenevix-Trench,
Antonis C Antoniou,
Kenneth Offit
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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.
PLoS Genetics 03/2013; 9(3):e1003173. · 8.69 Impact Factor
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Maya Ghoussaini,
Olivia Fletcher,
Kyriaki Michailidou,
Clare Turnbull,
Marjanka K Schmidt,
Ed Dicks, Joe Dennis,
Qin Wang,
Manjeet K Humphreys,
Craig Luccarini, [......],
Susan M Gerty,
Nikki J Graham,
Bruce A J Ponder,
Georgia Chenevix-Trench,
Paul D P Pharoah,
Mark Lathrop,
Alison M Dunning,
Nazneen Rahman,
Julian Peto,
Douglas F Easton
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ABSTRACT: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Nature Genetics 01/2012; 44(3):312-8. · 35.53 Impact Factor
