Eng Lawson, Azad Abul Kalam, Qiu Xin, Kong Qin Quinn, 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, Liu Geoffrey, Faluyi Olusola O
Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada, Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
Division of Applied Molecular Oncology, Ontario Cancer Institute-Princess Margaret Cancer Centre and University of Toronto, 610 University Ave, Toronto, Ontario M5G 2M9, Canada.
Carcinogenesis. 2015 Sep;36(9):956-62. doi: 10.1093/carcin/bgv073. Epub 2015 May 25.
Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated 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. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality. Validation and evaluation of this association in other cancer sites are warranted.
血管内皮生长因子（VEGF）/血管生成途径中的多态性先前已被认为与癌症风险、预后以及对包括食管腺癌在内的治疗反应有关。先前的食管腺癌研究集中于使用候选多态性，限制了新型多态性的发现。在此，我们应用标签单核苷酸多态性（tagSNP）方法来识别与食管腺癌预后相关的新的VEGF途径多态性，并在一组独立的食管腺癌患者队列中对其进行验证。在231例处于所有分期/治疗方案的食管腺癌患者中，对通过标签和预测功能评估选择的58个基因多态性（18个KDR、7个VEGFA和33个FLT1）进行基因分型。应用针对重要社会人口统计学和临床病理因素进行调整的Cox比例风险模型来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137例食管腺癌患者的独立队列中对显著相关的多态性进行验证。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KDR rs17709898与PFS显著相关（调整后风险比，aHR = 0.69，95%置信区间（CI）：0.53 - 0.90；P = 5.9×10⁻³）。FLT1 rs3794405和rs678714与OS显著相关（aHR分别为1.44，95% CI：1.04 - 1.99；P = 0.03和aHR = 1.50，95% CI：1.01 - 2.24；P = 0.045）。未发现VEGFA多态性与任何一种结局显著相关。经验证，FLT1 rs3794405仍与OS密切相关（aHR = 1.59，95% CI：1.04 - 2.44；P = 0.03）。FLT1 rs3794405与食管腺癌的OS显著相关，其中每个变异等位基因使死亡风险增加45% - 60%。有必要在其他癌症部位对这种关联进行验证和评估。
