Abstract 5065: Fine-mapping the HOXB region detects common variants tagging a rare coding allele: Evidence for synthetic association in prostate cancer

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The HOXB13 gene has been implicated in prostate cancer susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 prostate cancer cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with prostate cancer risk, described by rs117576373, OR 1.30, P = 2.62×10-14. Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene, G84E, rs138213197, which has been identified recently as a moderate penetrance prostate cancer susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility. Citation Format: Zsofia Kote-Jarai, Edward Saunders, Tokhir Dadaev, Daniel Leongamornlert, Sarah Jugurnauth-Little, Malgorzata Tymrakiewicz, Koveela Govindasami, Fredrik Wiklund, Ali Amin Al Olama, Sara Benlloch, The PRACTICAL Consortium, Douglas Easton, Keneth Muir, Rosalind Eeles. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: Evidence for synthetic association in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5065. doi:10.1158/1538-7445.AM2014-5065