Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
PLoS One. 2013 Apr 23;8(4):e61469. doi: 10.1371/journal.pone.0061469. Print 2013.
In this study, 27 genetic polymorphisms that were previously reported to be associated with clinical outcomes in colorectal cancer patients were investigated in relation to overall survival (OS) and disease free survival (DFS) in colorectal cancer patients from Newfoundland.
The discovery and validation cohorts comprised of 532 and 252 patients, respectively. Genotypes of 27 polymorphisms were first obtained in the discovery cohort and survival analyses were performed assuming the co-dominant genetic model. Polymorphisms associated with disease outcomes in the discovery cohort were then investigated in the validation cohort.
When adjusted for sex, age, tumor stage and microsatellite instability (MSI) status, four polymorphisms were independent predictors of OS in the discovery cohort MTHFR Glu429Ala (HR: 1.72, 95%CI: 1.04-2.84, p = 0.036), ERCC5 His46His (HR: 1.78, 95%CI: 1.15-2.76, p = 0.01), SERPINE1 -675indelG (HR: 0.52, 95%CI: 0.32-0.84, p = 0.008), and the homozygous deletion of GSTM1 gene (HR: 1.4, 95%CI: 1.03-1.92, p = 0.033). In the validation cohort, the MTHFR Glu429Ala polymorphism was associated with shorter OS (HR: 1.71, 95%CI: 1.18-2.49, p = 0.005), although with a different genotype than the discovery cohort (CC genotype in the discovery cohort and AC genotype in the validation cohort). When stratified based on treatment with 5-Fluorouracil (5-FU)-based regimens, this polymorphism was associated with reduced OS only in patients not treated with 5-FU. In the DFS analysis, when adjusted for other variables, the TT genotype of the ERCC5 His46His polymorphism was associated with shorter DFS in both cohorts (discovery cohort: HR: 1.54, 95%CI: 1.04-2.29, p = 0.032 and replication cohort: HR: 1.81, 95%CI: 1.11-2.94, p = 0.018).
In this study, associations of the MTHFR Glu429Ala polymorphism with OS and the ERCC5 His46His polymorphism with DFS were identified in two colorectal cancer patient cohorts. Our results also suggest that the MTHFR Glu429Ala polymorphism may be an adverse prognostic marker in patients not treated with 5-FU.
在这项研究中，我们调查了先前报道与结直肠癌患者临床结局相关的 27 个遗传多态性，以评估它们与纽芬兰结直肠癌患者的总生存（OS）和无病生存（DFS）之间的关系。
发现队列和验证队列分别包含 532 名和 252 名患者。首先在发现队列中获得 27 个多态性的基因型，并在共显性遗传模型假设下进行生存分析。然后在验证队列中研究与疾病结局相关的发现队列中的多态性。
调整性别、年龄、肿瘤分期和微卫星不稳定性（MSI）状态后，MTHFR Glu429Ala（HR：1.72，95%CI：1.04-2.84，p=0.036）、ERCC5 His46His（HR：1.78，95%CI：1.15-2.76，p=0.01）、SERPINE1 -675indelG（HR：0.52，95%CI：0.32-0.84，p=0.008）和 GSTM1 基因纯合缺失（HR：1.4，95%CI：1.03-1.92，p=0.033）这四个多态性是发现队列中 OS 的独立预测因子。在验证队列中，MTHFR Glu429Ala 多态性与较短的 OS 相关（HR：1.71，95%CI：1.18-2.49，p=0.005），尽管与发现队列的基因型不同（发现队列为 CC 基因型，验证队列为 AC 基因型）。当根据接受 5-氟尿嘧啶（5-FU）为基础的治疗方案进行分层时，该多态性仅与未接受 5-FU 治疗的患者的 OS 降低相关。在 DFS 分析中，当调整其他变量后，在两个队列中 ERCC5 His46His 多态性的 TT 基因型均与较短的 DFS 相关（发现队列：HR：1.54，95%CI：1.04-2.29，p=0.032；验证队列：HR：1.81，95%CI：1.11-2.94，p=0.018）。
在这项研究中，我们在两个结直肠癌患者队列中发现了 MTHFR Glu429Ala 多态性与 OS 以及 ERCC5 His46His 多态性与 DFS 之间的关联。我们的结果还表明，MTHFR Glu429Ala 多态性可能是未接受 5-FU 治疗的患者的不良预后标志物。
