Data from Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Kyriaki Michailidou,Antoinette Hollestelle,Siranoush Manoukian,Annika Lindblom,Qin Wang,M Pilar Zamora,Maria Kabisch,Martha J Shrubsole,Pascal Guénel,Sara Margolin,Susan L Neuhausen,Marjanka K Schmidt,Christopher A Haiman,Florentia Fostira,Arnaud Droit,Rita K Schmutzler,Peter Devilee,Stig E Bojesen,Thomas Brüning,Simon S Cross,Wanqing Wen,Thomas Choudary Putti,Artitaya Lophatananon,Paolo Peterlongo,Hatef Darabi,Sander Canisius,Fergus J Couch,Anja Rudolph,Hiltrud Brauch,Julia A Knight,Alison M Dunning,Barbara Burwinkel,Jirong Long,Elinor J Sawyer,Hermann Brenner,Daehee Kang,Robert Winqvist,Natalia Bogdanova,Douglas F Easton,Anna Jakubowska,Heli Nevanlinna,Cheng Har Yip,Ans Van Den Ouweland,Manjeet K Bolla,Siddhartha P Kar,Sofia Khan,Thilo Dörk,Silje Nord,Henrik Flyger,Maya Ghoussaini,Arto Mannermaa,Volker Arndt,Jiajun Shi,Matthias W Beckmann,Mervi Grip,Jacques Simard,Paul D.P Pharoah,Melissa C Southey,Irene L Andrulis,Bernard Thienpont,Roger L Milne,Thérèse Truong,Ji-Yeob Choi,Chenjie Zeng,Alfons Meindl,Hidemi Ito,Ying Zheng,Diether Lambrechts,Per Hall,Qiuyin Cai,Jingmei Li,Keitaro Matsuo,Suleeporn Sangrajrang,Peter A Fasching,Annegien Broeks,Nick Orr,Robert A.E.M Tollenaar,Ute Hamann,Angela Cox,Kenneth Muir,Chiu-Chen Tseng,Xingyi Guo,Kamila Czene,Nichola Johnson,Janet E Olson,John L Hopper,Graham G Giles,Olivia Fletcher,Anthony Swerdlow,Chen‐Yang Shen ,Chia‐Ni Hsiung ,Ian Tomlinson ,Jan Lubiński ,Alicia Beeghly–Fadiel ,William J Blot ,Loı̈c Le Marchand ,Anna H Wu ,Valérie Gaborieau ,Jenny Chang‐Claude ,Hui Cheng ,Soo‐Hwang Teo ,Montserrat García‐Closas ,Hoda Anton‐Culver ,Veli‐Matti Kosma ,Louise A Brinton ,Xiao‐Ou Shu ,Amanda E Toland ,Catriona Mclean ,Georgia Chenevix‐Trench ,Javier Benı́tez ,Frederik Marmé ,Zheng Wang

doi:10.1158/1055-9965.c.6515442.v1

Abstract

<div>AbstractBackground: 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.Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.Results: 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 (r2 ≥ 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.Conclusion: 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.Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.</div>

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