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Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

ABSTRACT: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ? 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

SUBMITTER: Guo X

PROVIDER: S-EPMC4633342 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

Guo Xingyi X Long Jirong J Zeng Chenjie C Michailidou Kyriaki K Ghoussaini Maya M Bolla Manjeet K MK Wang Qin Q Milne Roger L RL Shu Xiao-Ou XO Cai Qiuyin Q Beesley Jonathan J Kar Siddhartha P SP Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Beckmann Matthias W MW Beeghly-Fadiel Alicia A Benitez Javier J Blot William W Bogdanova Natalia N 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 Dörk 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 Grip Mervi M Guénel Pascal P Haiman Christopher A CA Hamann Ute U Hartman Mikael M Hollestelle Antoinette A Hopper John L JL Hsiung Chia-Ni CN Ito Hidemi H Jakubowska Anna A Johnson Nichola N Kabisch Maria M Kang Daehee D Khan Sofia S Knight Julia A JA Kosma Veli-Matti VM Lambrechts Diether D Le Marchand Loic L Li Jingmei J Lindblom Annika A Lophatananon Artitaya A Lubinski Jan J Mannermaa Arto A Manoukian Siranoush S Margolin Sara S Marme Frederik F Matsuo Keitaro K McLean Catriona A CA Meindl Alfons A Muir Kenneth K Neuhausen Susan L SL Nevanlinna Heli H Nord Silje S Olson Janet E JE Orr Nick N 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 Shi Jiajun J Shrubsole Martha J MJ Southey Melissa C MC Swerdlow Anthony A Teo Soo Hwang SH Thienpont Bernard B Toland Amanda Ewart AE Tollenaar Robert A E M RA Tomlinson Ian P M IP Truong Thérèse T Tseng Chiu-Chen CC van den Ouweland Ans A Wen Wanqing W Winqvist Robert R Wu Anna A Yip Cheng Har CH Zamora M Pilar MP Zheng Ying Y Hall Per P Pharoah Paul D P PD Simard Jacques J Chenevix-Trench Georgia G Dunning Alison M AM Easton Douglas F DF Zheng Wei W

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20150909 11

<h4>Background</h4>A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.<h4>Methods</h4>We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.<h4>Results</h4>Conditional analyses identified two independent association signals among women of European ance ...[more]

PMID: 26354892

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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.

Dataset Information

Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

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Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

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