Germline genetic variation in JAK2 as a prognostic marker in castration-resistant prostate cancer.

Autor: Zhang BY; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Riska SM; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA., Mahoney DW; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA., Costello BA; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Kohli R; Mayo High School, Rochester, MN, USA., Quevedo JF; Department of Oncology, Mayo Clinic, Rochester, MN, USA., Cerhan JR; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA., Kohli M; Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Jazyk: angličtina
Zdroj: BJU international [BJU Int] 2017 Mar; Vol. 119 (3), pp. 489-495. Date of Electronic Publication: 2016 Aug 06.
DOI: 10.1111/bju.13584
Abstrakt: Objectives: To evaluate the prognostic significance of germline variation in candidate genes in patients with castration-resistant prostate cancer (CRPC).
Methods: Germline DNA was extracted from peripheral blood mononuclear cells of patients with CRPC 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 a 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 (HRs) and 95% confidence intervals (CIs) under the additive allele model were estimated using Cox regression, adjusted for age at CRPC and Gleason score (GS).
Results: A total of 240 patients with CRPC were genotyped (14 genes; 84 SNPs). The median (range) age of the cohort was 69 (43-93) years. The GS distribution was 55% with GS ≥8, 32% with GS = 7 and 13% with GS <7 or unknown. The median (interquartile range) time from castration resistance to death for the cohort was 2.67 (1.6-4.07) years (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 < 3.2 × 10 -9 ).
Conclusions: Germline variation in the JAK2 gene was associated with survival in patients with CRPC and warrants further validation as a potential prognostic biomarker.
(© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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