Abstract A07: Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer

Abstract

Abstract We previously reported results from a case-control study nested in a large hospital-based cohort of men identified over a 12-year period (1990-2002) that gene promoter hypermethylation in histopathologically benign prostate specimens is a marker of prostate cancer risk (Tang et al. J Urol 2013). Whether methylation in pre-diagnostic benign prostate tissue can also predict subsequent disease prognosis has not been studied. Therefore, we estimated hazard ratios (HRs) for biochemical recurrence (BCR), defined as two successive prostate-specific antigen increases after definitive treatment, associated with methylation status of the two genes we found associated with prostate cancer risk: retinoic acid receptor-β (RARB) and adenomatosis polyposis coli (APC). Follow-up data were from a subset of the cases (n=394) that were part of our aforementioned nested prostate cancer case-control study of gene promoter methylation status of five genes measured in pre-diagnostic benign biopsy specimens. Overall, after adjusting for known clinical risk factors for prostate cancer progression (advanced grade, advanced stage, high prostate-specific antigen (PSA)), neither methylation of the APC or the RARB genes was associated with a significantly increased risk of BCR, but risk associated with RARB methylation was elevated (HR=1.30; 95% CI= 0.93-1.83). This risk was higher in Whites (HR=1.44; 95% CI= 0.92-2.25) compared with African Americans (HR=1.22; 95% CI= 0.71-2.12), but differences by race were not significant. In additional stratified analyses, we found that while associations with APC methylation did not differ between strata, RARB methylation showed significantly increased risk of BCR in specific substrata; specifically men with high PSA at time of diagnosis (HR=1.73; 95% CI=1.13–2.64) and men in whom methylation did not occur in the four other genes under study (HR=1.82; 95% CI=1.14–2.93). In conclusion, we show for the first time that methylation events occurring before onset of prostate cancer may predict the course of subsequent cancer in defined patient groups. These findings may have important clinical decision making implications in terms of both identifying aggressive prostate cancer at its earliest stages and also avoiding unnecessary additional diagnostic biopsies. Citation Format: Benjamin Rybicki, Michelle Jankowski, Kieu Do, Dhananjay Chitale, Sheri Trudeau, Andrew Rundle, Steven Belinsky, Deliang Tang. Methylation of RARB in prediagnosis benign tissue and risk of disease progression in men subsequently diagnosed with prostate cancer. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A07.