Abstract 4577: Identification of twenty three novel prostate cancer susceptibility loci using a custom assay (the icogs) in an international consortium: PRACTICAL.
Authors: Rosalind A. Eeles, Zsofia Kote-jarai, The PRACTICAL Consortium
Journal: Cancer Research (2013)

Abstract Identification Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we genotyped 211,155 SNPs on a custom chip (iCOGS) in blood DNA from 25,074 PrCa cases and 24,272 controls from 32 studies in the international PRACTICAL consortium. The chip was composed of GWAS hits from a meta analysis of 4 GWAS [11,085 cases and 11,463 controls from UK,Australia, Cancer Genetic Markers of Susceptibility (CGEMS); Cancer of the Prostate in Sweden (CAPS) and the Breast and Prostate Cancer Cohort Consortium (BPC3)], fine mapping of known regions and genes in candidate pathways. Results from the GWAS component are reported here. Twenty-three new PrCa susceptibility loci were identified at genome-wide significance (P&amp;lt;5x10-8). Neighbouring genes include MDM4, NOTCH4, MMP7, RAD51L1, SPOP and HOXB13. There was no strong evidence for heterogeneity in the per-allele OR among studies. All alleles are common (MAF 8-49%) with per allele ORs from 1.06 to 1.15. All but two exhibit a pattern of association consistent with a log-additive model, as observed for most common cancer susceptibility alleles. Aggressive disease was defined as Gleason score &amp;gt; 8, PSA &amp;gt;100, disease stage of distant (i.e. outside the pelvis) or death from PrCa. The majority of SNPs showed clear association when analysis was restricted to aggressive disease (13 SNPs significant at P&amp;lt;.01) and for 22 of the 23 SNPs the estimated OR was in the same direction for aggressive and non-aggressive disease. Two SNPs were associated with PSA level in controls. Six SNPs showed a trend in OR with age at diagnosis, with a higher OR at younger ages. GeneGo pathway enrichment analysis showed the most strongly associated pathways were cell adhesion (P=1.31 x10−6), extracellular matrix (ECM) remodelling (P=3.6x10−9), and transcriptional regulation by androgen receptor (P= 3.5x10−8). Comparison of the direction of effects in the GWAS and COGS replication stages indicate that more than 1800 loci on the array are associated with this disease. More than 70 PrCa susceptibility loci, explaining 30% of the familial risk in this disease, have now been identified. Based on the combined risks conferred by these loci, the top 1% of the risk distribution has a 4.7fold increased risk compared with the average of the population. These results will facilitate population risk stratification for clinical studies. Citation Format: Rosalind A. Eeles, Zsofia Kote-jarai, The PRACTICAL Consortium. Identification of twenty three novel prostate cancer susceptibility loci using a custom assay (the icogs) in an international consortium: PRACTICAL. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4577. doi:10.1158/1538-7445.AM2013-4577