To evaluate the prognostic significance of germline variation in candidate genes in patients with castration-resistant prostate cancer (CRPC).
Germline DNA was extracted from peripheral blood mononuclear cells of CRPC patients enrolled in a clinically annotated registry. Fourteen candidate genes implicated in either initiation or progression of prostate cancer were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of >5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP level results the per allele hazard ratios (HR) and 95% confidence intervals (CI) under the additive allele model were estimated using Cox regression adjusted for age at CRPC and Gleason score (GS).
Two hundred and forty two CRPC patients were genotyped (14 genes; 84 SNPs). The median age of the cohort was 69 years (range 43-93). The GS distribution was 55% with GS≥8, 32% with GS=7 and 13% with GS<7 or unknown. Median time from castration resistance to death for the cohort was 2.67 years (IQ range: 1.6-4.07, 144 deaths). At the gene level a single gene, JAK2 was associated with OS (P<0.01), and 11 of 18 JAK2 SNPs were individually associated with OS after adjustment for age and GS. A multivariate model consisting of age, GS, rs2149556 (HR=0.67; 95% CI 0.38-1.18), and rs4372063 (HR=2.17; 95% CI 1.25-3.76) was constructed to predict survival in patients with CRPC (concordance of 0.69, p<3.2x10(-9) ).
Germline variation in the JAK2 gene is associated with survival in CRPC patients and warrants further validation as a potential prognostic biomarker. This article is protected by copyright. All rights reserved.
BJU international. 2016 Jul 13 [Epub ahead of print]
Ben Y Zhang, Shaun M Riska, Douglas W Mahoney, Brian A Costello, Rhea Kohli, J F Quevedo, James R Cerhan, Manish Kohli
Department of Oncology, Mayo Clinic, Rochester, MN., Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Department of Oncology, Mayo Clinic, Rochester, MN., Mayo High School, Mayo High School, 1420 11th Avenue SE, Rochester, MN, 55904., Department of Oncology, Mayo Clinic, Rochester, MN., Department of Health Sciences Research, Mayo Clinic, Rochester, MN., Department of Oncology, Mayo Clinic, Rochester, MN.