Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
Int J Cancer. 2014 Oct 1;135(7):1625-33. doi: 10.1002/ijc.28796. Epub 2014 Mar 6.
We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p = 0.005, eleven cohorts) and MSS (HR = 1.20 per allele, 95% CI 1.01-1.39, p = 0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS.
我们报告了位于多聚（腺苷二磷酸核糖）聚合酶 1（PARP1）基因上游的遗传变异（rs2249844）与 11 个 BioGenoMEL 黑色素瘤队列中生存的关联。该基因编码一种参与多种细胞过程的蛋白质，包括单链 DNA 修复。使用比例风险回归对每个队列进行生存分析，调整了与生存相关的已知因素。生存被测量为总生存（OS），并且在可用的情况下，测量黑色素瘤特异性生存（MSS）。使用随机效应荟萃分析合并结果。通过测试来自福尔马林固定石蜡包埋肿瘤的基因表达水平，研究了 PARP1 蛋白在黑色素瘤溃疡和生存中的作用的证据。rs2249844 中 PARP1 罕见变异的遗传与 OS（危险比（HR）= 1.16/等位基因，95%置信区间（CI）1.04-1.28，p = 0.005，11 个队列）和 MSS（HR = 1.20/等位基因，95%CI 1.01-1.39，p = 0.03，8 个队列）呈显著关联。我们报告了支持 rs2249844 具有功能效应的生物信息学数据。肿瘤中 PARP1 基因表达水平较高与肿瘤溃疡和较差的 OS 相关。
