Faluyi Olusola O, Eng Lawson, Qiu Xin, Che Jiahua, Zhang Qihuang, Cheng Dangxiao, Ying Nanjiao, Tse Alvina, Kuang Qin, Dodbiba Lorin, Renouf Daniel J, Marsh Sharon, Savas Sevtap, Mackay Helen J, Knox Jennifer J, Darling Gail E, Wong Rebecca K S, Xu Wei, Azad Abul Kalam, Liu Geoffrey
Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Cancer Med. 2017 Feb;6(2):361-373. doi: 10.1002/cam4.989. Epub 2017 Jan 11.
Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort but had consistent associations in the pooled cohort. Larger studies are required to confirm/validate the prognostic value of these polymorphisms in esophageal adenocarcinoma.
微小RNA（miRNA）及其通路基因的多态性此前已被证明与癌症风险和预后相关，但尚未在食管腺癌的预后方面进行研究。在此，我们评估候选miRNA通路多态性与食管腺癌预后的关系，并试图在一个独立的食管腺癌患者队列中进行验证。在231例处于所有分期/治疗方案的食管腺癌患者中，对38个候选基因多态性（17个生物发生相关、9个miRNA靶标、5个初级miRNA、7个前体miRNA）进行基因分型和分析。通过对社会人口统计学和临床病理协变量进行校正的Cox比例风险模型，有助于评估基因多态性与总生存期（OS）和无进展生存期（PFS）的关联。然后在一个由137例食管腺癌患者组成的独立队列中评估显著相关的多态性。在231例发现队列患者中，86%为男性，中位诊断年龄为64岁，34%在诊断时已发生转移，中位OS和PFS分别为20个月和12个月。发现GEMIN3 rs197412（风险比[HR]=1.37，95%置信区间[CI]：[1.04 - 1.80]；P=0.02）、hsa - mir - 124 - 1 rs531564（HR=0.60，95% CI：[0.53 - 0.90]；P=0.05）和KIAA0423 rs1053667（HR=0.51，95% CI：[0.28 - 0.96]；P=0.04）与OS相关。此外，发现GEMIN3 rs197412（HR=1.33，95% CI：[1.03 - 1.74]；P=0.03）和KRT81 rs3660（HR=1.29，95% CI：[1.01 - 1.64]；P=0.04）与PFS相关。尽管这些多态性在第二个队列中均无显著意义，但hsa - mir - 124 - 1 rs531564和KIAA0423 rs1053667呈现相同方向的趋势；当两个队列合并在一起时，GEMIN3 rs197412、hsa - mir - 124 - 1 rs531564和KIAA0423 rs1053667仍与OS显著相关。我们在一个患者发现队列中证明了多个miRNA通路多态性与食管腺癌预后的关联，该关联在一个单独队列中未得到验证，但在合并队列中具有一致的相关性。需要更大规模的研究来确认/验证这些多态性在食管腺癌中的预后价值。
