Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk
Authors: Guo Xingyi , Long Jirong , Zeng Chenjie , Michailidou Kyriaki , Ghoussaini Maya , Bolla Manjeet K. , Wang Qin , Milne Roger L. , Shu Xiao-Ou , Cai Qiuyin , Beesley Jonathan , Kar Siddhartha P. , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Beckmann Matthias W. , Beeghly-Fadiel Alicia , Benitez Javier , Blot William , Bogdanova Natalia , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Brinton Louise , Broeks Annegien , Brüning Thomas , Burwinkel Barbara , Cai Hui , Canisius Sander , Chang-Claude Jenny , Choi Ji-Yeob , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Darabi Hatef , Devilee Peter , Droit Arnaud , Dörk Thilo , Fasching Peter A. , Fletcher Olivia , Flyger Henrik , Fostira Florentia , Gaborieau Valerie , García-Closas Montserrat , Giles Graham G. , Grip Mervi , Guénel Pascal , Haiman Christopher A. , Hamann Ute , Hartman Mikael , Hollestelle Antoinette , Hopper John L. , Hsiung Chia-Ni , Ito Hidemi , Jakubowska Anna , Johnson Nichola , Kabisch Maria , Kang Daehee , Khan Sofia , Knight Julia A. , Kosma Veli-Matti , Lambrechts Diether , Le Marchand Loic , Li Jingmei , Lindblom Annika , Lophatananon Artitaya , Lubinski Jan , Mannermaa Arto , Manoukian Siranoush , Margolin Sara , Marme Frederik , Matsuo Keitaro , McLean Catriona A. , Meindl Alfons , Muir Kenneth , Neuhausen Susan L. , Nevanlinna Heli , Nord Silje , Olson Janet E. , Orr Nick , Peterlongo Paolo , Putti Thomas Choudary , Rudolph Anja , Sangrajrang Suleeporn , Sawyer Elinor J. , Schmidt Marjanka K. , Schmutzler Rita K. , Shen Chen-Yang , Shi Jiajun , Shrubsole Martha J. , Southey Melissa C. , Swerdlow Anthony , Teo Soo Hwang , Thienpont Bernard , Toland Amanda Ewart , Tollenaar Robert A.E.M. , Tomlinson Ian P.M. , Truong Thérèse , Tseng Chiu-chen , van den Ouweland Ans , Wen Wanqing , Winqvist Robert , Wu Anna , Yip Cheng Har , Zamora M. Pilar , Zheng Ying , Hall Per , Pharoah Paul D.P. , Simard Jacques , Chenevix-Trench Georgia ,   on behalf of kConFab Investigators, Dunning Alison M. , Easton Douglas F. , Zheng Wei 
Published: September 2015

Abstract
Background: 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.