Department of Medical Oncology, Princess Margaret Hospital, Toronto, Ontario; Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
J Gastroenterol Hepatol. 2013 Sep;28(9):1482-8. doi: 10.1111/jgh.12286.
Although gastroesophageal reflux disease (GERD) is a risk factor for esophageal adenocarcinoma (EAC), some patients develop EAC in the absence of GERD. A putative mechanism of reflux-induced tumorigenesis involves disruptions in the p53 pathway. We assessed the interaction of GERD and p53 pathway polymorphisms on EAC prognosis.
In a prospective cohort of 358 EAC patients, clinical data (including GERD history and survival) were collected. Germline DNA was genotyped for MDM2 T309G and p53 Arg72Pro. Cox proportional hazards models were used to determine adjusted hazard ratios (AHR) for associations between genotype, GERD, and genotype-GERD interactions with survival.
Compared with other genotypes, MDM2 G/G (median overall survival 21 vs 30 months; P < 0.001) and p53 Pro/Pro (12 vs 30 months; P = 0.004) were associated with shorter survival. When analyzed by GERD, MDM2 G/G was associated with shorter survival in patients without GERD (AHR 3.4, 95% CI 2.0-6.0), but not in patients with GERD (AHR 1.1 [0.7-1.8]); the MDM2-GERD interaction was significant (P = 0.003). A similar trend was seen for p53 Pro/Pro (AHRs 2.5 without GERD vs 1.4 with GERD). Combined analysis of at-risk variants (MDM2 G or p53 Pro), revealed each additional at-risk variant was associated with shorter survival in patients without GERD (AHR 1.6) but not with GERD (AHR 1.0).
MDM2 G/G and the combination of MDM2 G and p53 Pro were negative prognostic factors for EAC patients without GERD but not for those with GERD. There may be biological differences between GERD positive and GERD negative EAC.
尽管胃食管反流病（GERD）是食管腺癌（EAC）的危险因素，但有些患者在没有 GERD 的情况下也会发生 EAC。反流引起肿瘤发生的一个假设机制涉及 p53 途径的中断。我们评估了 GERD 和 p53 途径多态性对 EAC 预后的相互作用。
在 358 例 EAC 患者的前瞻性队列中，收集了临床数据（包括 GERD 病史和生存情况）。对 MDM2 T309G 和 p53 Arg72Pro 的种系 DNA 进行了基因分型。Cox 比例风险模型用于确定基因型、GERD 与基因型-GERD 相互作用与生存之间的关联的调整风险比（AHR）。
与其他基因型相比，MDM2 G/G（中位总生存期 21 与 30 个月；P<0.001）和 p53 Pro/Pro（12 与 30 个月；P=0.004）与较短的生存相关。按 GERD 分析时，MDM2 G/G 与无 GERD 的患者的生存时间较短相关（AHR 3.4，95%CI 2.0-6.0），但与 GERD 患者无关（AHR 1.1 [0.7-1.8]）；MDM2-GERD 相互作用具有显著性（P=0.003）。p53 Pro/Pro 也有类似的趋势（无 GERD 的 AHR 为 2.5，GERD 的 AHR 为 1.4）。对高危变异（MDM2 G 或 p53 Pro）的联合分析显示，无 GERD 的患者每增加一个高危变异与生存时间较短相关（AHR 1.6），但与 GERD 无关（AHR 1.0）。
MDM2 G/G 和 MDM2 G 与 p53 Pro 的组合是无 GERD 的 EAC 患者的不良预后因素，但不是 GERD 患者的预后因素。GERD 阳性和 GERD 阴性 EAC 之间可能存在生物学差异。
