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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

ABSTRACT: Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR?=?0.95, 95% CI?=?0.93-0.97, conditional p?=?5.8 × 10(-6) ), rs7815245 (OR?=?0.94, 95% CI?=?0.91-0.96, conditional p?=?1.1 × 10(-6) ) and rs2033101 (OR?=?1.05, 95% CI?=?1.02-1.07, conditional p?=?1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) ?=?0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

SUBMITTER: Shi J

PROVIDER: S-EPMC5110427 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

Shi Jiajun J Zhang Yanfeng Y Zheng Wei W Michailidou Kyriaki K Ghoussaini Maya M Bolla Manjeet K MK Wang Qin Q Dennis Joe J Lush Michael M Milne Roger L RL Shu Xiao-Ou XO Beesley Jonathan J Kar Siddhartha S Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Beckmann Matthias W MW Zhao Zhiguo Z Guo Xingyi X Benitez Javier J Beeghly-Fadiel Alicia A Blot William W Bogdanova Natalia V NV Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Brinton Louise L Broeks Annegien A Brüning Thomas T Burwinkel Barbara B Cai Hui H Canisius Sander S Chang-Claude Jenny J Choi Ji-Yeob JY Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Darabi Hatef H Devilee Peter P Droit Arnaud A Dork Thilo T Fasching Peter A PA Fletcher Olivia O Flyger Henrik H Fostira Florentia F Gaborieau Valerie V García-Closas Montserrat M Giles Graham G GG Guenel Pascal P Haiman Christopher A CA Hamann Ute U Hartman Mikael M Miao Hui H Hollestelle Antoinette A Hopper John L JL Hsiung Chia-Ni CN Ito Hidemi H Jakubowska Anna A Johnson Nichola N Torres Diana D Kabisch Maria M Kang Daehee D Khan Sofia S Knight Julia A JA Kosma Veli-Matti VM Lambrechts Diether D Li Jingmei J Lindblom Annika A Lophatananon Artitaya A Lubinski Jan J Mannermaa Arto A Manoukian Siranoush S Le Marchand Loic L Margolin Sara S Marme Frederik F Matsuo Keitaro K McLean Catriona C Meindl Alfons A Muir Kenneth K Neuhausen Susan L SL Nevanlinna Heli H Nord Silje S Børresen-Dale Anne-Lise AL Olson Janet E JE Orr Nick N van den Ouweland Ans M W AMW Peterlongo Paolo P Putti Thomas Choudary TC Rudolph Anja A Sangrajrang Suleeporn S Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Shen Chen-Yang CY Hou Ming-Feng MF Shrubsole Matha J MJ Southey Melissa C MC Swerdlow Anthony A Teo Soo Hwang SH Thienpont Bernard B Toland Amanda E AE Tollenaar Robert A E M RAEM Tomlinson Ian I Truong Therese T Tseng Chiu-Chen CC Wen Wanqing W Winqvist Robert R Wu Anna H AH Yip Cheng Har CH Zamora Pilar M PM Zheng Ying Y Floris Giuseppe G Cheng Ching-Yu CY Hooning Maartje J MJ Martens John W M JWM Seynaeve Caroline C Kristensen Vessela N VN Hall Per P Pharoah Paul D P PDP Simard Jacques J Chenevix-Trench Georgia G Dunning Alison M AM Antoniou Antonis C AC Easton Douglas F DF Cai Qiuyin Q Long Jirong J

International journal of cancer 20160617 6

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represente ...[more]

PMID: 27087578

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Project description:BackgroundMultiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.MethodWe performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.ResultsAnalysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.ConclusionThis study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

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Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.

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