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

Xingyi Guo, Jirong Long, Chenjie Zeng, Kyriaki Michailidou, Maya Ghoussaini, Manjeet K Bolla, Qin Wang, Roger L Milne, Xiao-Ou Shu, Qiuyin Cai, Jonathan Beesley, Siddhartha P Kar, Irene L Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, William Blot, Natalia BogdanovaStig E Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Hui Cai, Sander Canisius, Jenny Chang-Claude, Ji-Yeob Choi, Fergus J Couch, Angela Cox, Simon S Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Arnaud Droit, Thilo Dörk, Peter A Fasching, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Valerie Gaborieau, Montserrat García-Closas, Graham G Giles, Mervi Grip, Pascal Guénel, Christopher A Haiman, Ute Hamann, kConFab Investigators

21 Citationer (Scopus)

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 (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.

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.

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