Abstract SY32-02: Genetic predisposition to prostate cancer (PrCa) and its clinical application
Authors: Eeles Rosalind A. 
Published: May 2015

Abstract
There is evidence for a genetic predisposition to PrCa from epidemiological and twin studies. There is an increased risk to unaffected relatives of cases. We now know that there are common genetic variants which each confer a small risk but which can cumulatively confer quite substantial risks in those who have a genetic profile in the top 10% of the population risk distribution. 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. Twenty-three new PrCa susceptibility loci were identified at genome-wide significance (P&lt;5x10-8). This brought the number of currently known genetic variants associated with PrCa to a total of 76. All alleles are common (8-49% of the population) 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, defined as Gleason score &gt; 8, PSA &gt;100, disease stage of distant (i.e. outside the pelvis) or death from PrCa was associated with 16 of the variants; P&lt;.05. 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. The 76 common PrCa susceptibility loci now explain 30% of the familial risk in this disease. 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 and the top 10%, 2.7-fold. There are also rarer variants which confer higher risks and many of these are in the DNA repair pathway. About 1.2% of PrCa cases diagnosed at &lt;65 years are due to germline mutations in the breast/ovarian cancer predisposition genes, BRCA1 and BRCA2 (the lifetime risks of germline mutations in these genes are approximately 3-8 fold respectively), and there is increasing evidence that the mismatch repair genes which predispose to Lynch syndrome also increase PrCa risk about 2-3 fold lifetime. The clinical behaviour of PrCa due to these rarer mutations could affect management as they are associated with more aggressive disease and those associated BRCA2 have been shown to have a poorer prognosis. These results will facilitate population risk stratification for clinical studies in screening and cancer care.
Citation Format: Rosalind A. Eeles. Genetic predisposition to prostate cancer (PrCa) and its clinical application. [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 SY32-02. doi:10.1158/1538-7445.AM2014-SY32-02