Do genetic polymorphisms predict risk of recurrence in patients with localized renal cell carcinoma? Results from a cohort study.

Abstract

4506 Background: Gene polymorphisms in critical signaling pathways may impact recurrence in patients with localized renal cell cancer (RCC) Methods: Germline DNA was extracted from 425 patients of European-American ancestry that were enrolled in a prospective protocol with full baseline and follow up clinical data. Using the Sequenom iPLEX Gold platform, genotyping was performed for select genes involved in RCC pathogenesis, angiogenesis, metabolism, and immune regulation, including VHL, HIF-1, HIF-2, VEGF, VEGFR-2, CAIX, mTOR, PI3K, CTLA4, PD1, and B7H1. The primary endpoint was recurrence free interval (RFI), defined as time from surgery to recurrence or last follow-up. Cox Proportional Hazards model was used to evaluate and identify single nucleotide polymorphisms (SNPs) associated with RFI. A multivariate model adjusted for clinical factors which predict recurrence. The false discovery rate (pFDR) was used to control for the number of tests performed. With 45% RFI events, and 10% variant prevalence, there was 86% power to detect HR=2.0 (two sided alpha=0.05) Results: The median follow-up time was 49.1 months. Clinical factors associated with RFI included age at diagnosis (log-rank p=0.02), clinical stage (p<0.001), Fuhrman nuclear grade (p<0.001), performance status (p<0.001), and tumor size (p<0.001). Three SNPs in 2 genes were found to be highly predictive of RFI in univariate analysis; HIF2A (2 SNPs with p=6.00 E-4 for each) and ABCB1 (1 SNP with p=3.00 E-4). The prognostic features of these SNPs remain significant after adjusting for clinical factors (p=0.004 for the SNP in the ABCB1 gene and p=0.009 for the SNPs in the HIF-2 gene). The SNP associated with the highest recurrence risk resides in the ABCB1 gene, which codes for the multidrug resistance P-glycoprotein. Homozygotes for the risk haplotype have an adjusted HR of 2.88 (95% CI, 1.4-5.9; p=.004) for shorter RFI, compared to patients with other haplotypes Conclusions: This is the first study to implicate germline variations in critical signaling pathways with cancer recurrence in patients with localized RCC. Validation of these findings in an independent population is planned.