Abstract 2782: Genetic susceptibility to prostate cancer progression and relationship with PSA level: Case-case study

Abstract

Abstract Purpose: Prostate cancer is a mixture of progressive and non-progressive cancers. To date, genome-wide association studies have identified more than 30 common susceptibility variants associated with the risk of prostate cancer. However, case-control study designs have failed to identify variants consistently associated with aggressive cancer. The aim of this study is to investigate whether prostate cancer susceptibility variants distinguish between progressive and non-progressive cancers, using case-case study design. Methods: We genotyped 85 prostate cancer susceptibility variants in 4,856 men with prostate cancer identified from the Prostate Testing for Cancer and Treatment (ProtecT), Prostate Cancer Mechanisms of Progression and Treatment (ProMPT), and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) studies. Men with advanced stage (T3-T4) (n=624), or Gleason score ≥ 7 (n=1,792) prostate cancer were compared to those with localised stage (T1-T2) (n=3,805), or Gleason score <7 (n=2,090) cancer, respectively, using logistic regression to estimate the odds ratio (OR) associated with risk allele and genotype, after controlling for age at diagnosis, PSA level at diagnosis, stage and / or Gleason score. Results: On univariate analysis, three variants (rs16901979, rs10896449, rs2735839) were associated with stage, and six (rs1447295, rs16901979, rs10896449, rs2735839 rs17181356 rs3760511) with Gleason score. In multivariate analysis, the variant rs2735839 at 19q13 in KLK2/3 region was associated with 42% increase in the odds for advanced stage cancer (adjusted OR per allele =1.42; 95% CI 1.08-1.87; ptrend =0.01). However, there was evidence of interaction with PSA level (p<0.001). The adjusted OR for rs2735839 for advanced compared to localised cancers among those with PSA ≥10ng/ml was 1.79 (95% CI 1.26-2.54; p=0.001), whereas among those with PSA<10ng/ml, the OR was 0.96 (95% CI 0.60-1.56; p=0.88). Whereas the variant rs3760511 at 17q12 was associated with reduced risk for high Gleason score cancer (adjusted OR per allele=0.85 95% CI 0.75-0.96; ptrend =0.01). Conclusion: The interaction between PSA level and stage may inform the underlying biological mechanism for cancer progression in stage. These findings may also have clinical utility in identifying tumours with and without the potential for progression to advanced stage or higher Gleason score. Further validation in larger studies would be needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2011-2782