Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk
Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk
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DOI：
10.1002/ijc.28160
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发表时间：
2013-10-01
影响因子：
6.4
通讯作者：
Peters, Wilbert H. M.
中科院分区：
文献类型：
--
作者：
Dura, Polat;van Veen, Elke M.;Peters, Wilbert H. M.
Barrett食管以胃食管反流病和肥胖为危险因素，易患食管腺癌（EAC）。最近，英国全基因组关联研究确定了两个Barrett食管易感基因座，该基因座位于主要组织相容性复合体（MHC; rs 9257809）内，并与Forkhead-F1（FOXF 1; rs 9936833）编码基因密切相关。一个有趣的问题是与巴雷特食管相关的多态性是否也与食管癌（EC），更具体地说是EAC的发生有关。评估个体遗传易感性可以帮助识别更容易从监测计划中受益的高风险患者。我们的假设：Barrett相关的MHC和FOXF 1变异改变了高加索人的EC风险。在荷兰的一项病例对照研究中，纳入了431例EC患者和605例健康对照。采用实时荧光定量PCR（RT-PCR）方法检测6p 21（MHC）和16 q24（FOXF 1）的多态性。采用Logistic回归分析计算比值比和95%置信区间。FOXF 1 rs 9936833变体C等位基因与EAC易感性增加相关; OR，[95% CI]; 1.21，[0.99-1.47]。性别分层分析显示，男性中存在类似的相关性; 1.24 [1.00-1.55]。变异的MHC rs 9257809 G等位基因以及MHC杂合AG基因型显著增加ESCC风险;分别为1.76 [1.16-2.66]和1.74 [1.08-2.80]。性别分层显示变异G等位基因尤其存在于女性患者中; 2.32 [1.04-5.20]。总之，本研究提供的证据表明，与Barrett食管相关的MHC rs 9257809和FOXF 1 rs 9936833变异也增加了高加索人ESCC和EAC的易感性。FOX蛋白是参与胃肠道器官形成的转录因子，而MHC单倍型与吸烟行为密切相关，吸烟行为是ESCC的关键危险因素。评估个体遗传易感性可以帮助识别更容易从（巴雷特）监测项目中获益的高危患者。识别具有增加食管癌易感性的遗传变异的患者可以使食管癌监测计划更加有效。在这里，两个变异，巴雷特相关的MHC rs 9257809和FOXF 1 rs 9936833，据报道，增加食管腺癌（ECA）和鳞状细胞癌（ESCC）的易感性在高加索人。两者都有合理的机制来支持它们的参与，已知FOX蛋白与胃肠道的器官发生相关，某些主要组织相容性（MHC）单倍型与吸烟行为相关，这是ESCC的关键风险因素。
Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.What's new? Identifying patients with genetic variants that heighten susceptibility to carcinoma of the esophagus could make esophageal cancer surveillance programs more effective. Here, two variations, Barrett-associated MHC rs9257809 and FOXF1 rs9936833, are reported to increase esophageal adenocarcinoma (ECA) and squamous cell carcinoma (ESCC) susceptibility in Caucasians. Both have plausible mechanisms to support their involvement, with FOX proteins known to be associated with in organogenesis of the gastrointestinal tract and certain major histocompatibility (MHC) haplotypes associated with smoking behavior, a crucial risk factor for ESCC.