Hardie Laura J, Darnton S Jane, Wallis Yvonne L, Chauhan Anita, Hainaut Pierre, Wild Christopher P, Casson Alan G
Molecular Epidemiology Unit and Health Services Research, School of Medicine, Algernon Firth Building, University of Leeds, Leeds LS2 9JT, UK.
Cancer Lett. 2005 Jan 20;217(2):221-30. doi: 10.1016/j.canlet.2004.06.025.
Alteration of the p16 tumor suppressor gene has been implicated as a critical lesion in the molecular pathogenesis of esophageal adenocarcinoma. The aim of this study was to characterize the spectrum of p16 alterations in surgically resected esophageal tissues, comprising histologically normal esophageal squamous and gastric epithelia, premalignant Barrett's epithelia, and associated esophageal adenocarcinomas, and to explore associations between p16 mRNA expression and p16 mutations, deletions, promoter hypermethylation, p16 protein expression, and clinico-pathologic features for the same tissues. We have shown that while p16 mutations are uncommon (2%; 1/54), hypermethylation of the p16 promoter is detected in 43% (9/21) of histologically normal epithelia, in 77% (14/18) of associated Barrett's epithelia, and in 85% (18/21) of esophageal adenocarcinomas. However, p16 mRNA levels (relative to matched normal epithelia) were variable in Barrett's epithelia and adenocarcinomas, having no clear correlation with methylation status or other molecular and clinico-pathological parameters. These findings are consistent with a role for the p16 tumor suppressor gene early in the molecular progression of Barrett's epithelium to invasive esophageal adenocarcinoma, but do not support the notion that the detection of hypermethylation is systematically associated with low levels of expression.
p16肿瘤抑制基因的改变被认为是食管腺癌分子发病机制中的关键病变。本研究的目的是明确手术切除的食管组织中p16改变的情况，这些组织包括组织学上正常的食管鳞状上皮和胃上皮、癌前病变的巴雷特上皮以及相关的食管腺癌，并探讨同一组织中p16 mRNA表达与p16突变、缺失、启动子高甲基化、p16蛋白表达及临床病理特征之间的关联。我们发现，虽然p16突变并不常见（2%；1/54），但在组织学正常的上皮中，43%（9/21）检测到p16启动子高甲基化，在相关的巴雷特上皮中为77%（14/18），在食管腺癌中为85%（18/21）。然而，巴雷特上皮和腺癌中p16 mRNA水平（相对于匹配的正常上皮）存在差异，与甲基化状态或其他分子及临床病理参数无明显相关性。这些发现与p16肿瘤抑制基因在巴雷特上皮向浸润性食管腺癌分子进展早期所起的作用一致，但不支持高甲基化检测与低表达水平系统性相关的观点。
