title: Germline genetic variation in JAK2 as a prognostic marker in castration-resistant prostate cancer.
abstract: 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 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).
  
  
  
  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).
  
  
  
  Germline variation in the JAK2 gene was associated with survival in patients with CRPC and warrants further validation as a potential prognostic biomarker.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ben Y
authors.initials: BY
authors.lastname: Zhang
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Shaun M
authors.initials: SM
authors.lastname: Riska
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Mahoney
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Costello
authors.affiliation: Mayo High School, Rochester, MN, USA.
authors.forename: Rhea
authors.initials: R
authors.lastname: Kohli
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jorge F
authors.initials: JF
authors.lastname: Quevedo
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Cerhan
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Kohli
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: 
  JAK2
  ; castration-resistant prostate cancer; germline mutations; prognosis