Zhang Ben Y, Riska Shaun M, Mahoney Douglas W, Costello Brian A, Kohli Rhea, Quevedo Jorge F, Cerhan James R, Kohli Manish
Department of Oncology, Mayo Clinic, Rochester, MN, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
BJU Int. 2017 Mar;119(3):489-495. doi: 10.1111/bju.13584. Epub 2016 Aug 6.
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 ).
Germline variation in the JAK2 gene was associated with survival in patients with CRPC and warrants further validation as a potential prognostic biomarker.
评估去势抵抗性前列腺癌（CRPC）患者候选基因种系变异的预后意义。
从纳入临床注释登记处的CRPC患者外周血单个核细胞中提取种系DNA。使用来自HapMap的单核苷酸多态性（SNP）对14个与前列腺癌发生或进展相关的候选基因进行标记，次要等位基因频率>5%。主要终点为总生存期（OS），定义为从CRPC发生到死亡的时间。主成分分析用于基因水平的显著性检验。对于SNP水平的结果，使用Cox回归估计加性等位基因模型下的每个等位基因风险比（HR）和95%置信区间（CI），并根据CRPC时的年龄和 Gleason评分（GS）进行调整。
共对240例CRPC患者进行了基因分型（14个基因；84个SNP）。该队列的中位（范围）年龄为69（43 - 93）岁。GS分布为：GS≥8者占55%，GS = 7者占32%，GS<7或未知者占13%。该队列从去势抵抗到死亡的中位（四分位间距）时间为2.67（1.6 - 4.07）年（144例死亡）。在基因水平上，单个基因JAK2与OS相关（P < 0.01），在调整年龄和GS后，18个JAK2 SNP中的11个分别与OS相关。构建了一个由年龄、GS、rs2149556（HR 0.67；95% CI 0.38 - 1.18）和rs4372063（HR 2.17；95% CI 1.25 - 3.76）组成的多变量模型来预测CRPC患者的生存情况（一致性为0.69，P < 3.2×10 ）。
JAK2基因的种系变异与CRPC患者的生存相关，作为一种潜在的预后生物标志物值得进一步验证。
