Milne Anya N A, Carvalho Ralph, Morsink Folkert M, Musler Alex R, de Leng Wendy W J, Ristimäki Ari, Offerhaus G Johan A
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Mod Pathol. 2006 Apr;19(4):564-72. doi: 10.1038/modpathol.3800563.
Many studies examine the molecular genetics of gastric cancer, but few look at young patients in particular and there is no comparison of molecular expression between early-onset gastric cancer (< or = 45 years old) and conventional gastric cancers. Expression of cycloxygenase-2 (COX-2) is elevated in gastric adenocarcinomas compared to non-neoplastic mucosa, and in light of studies showing reduced risk of gastric cancer in nonsteroidal anti-inflammatory drug users, we have chosen to investigate the expression of COX-2 and related molecules in 113 early-onset gastric cancers and compare it with 91 conventional gastric cancers, using tissue microarrays. These markers include molecules known to be important in conventional gastric carcinogenesis, such as E-Cadherin, p53, COX-2, Trefoil Factor-1 (TFF1), beta-catenin, p16 and c-myc; as well as molecules not yet described as being important in gastric cancer, such as the transcription factor c-jun, the COX-2 mRNA stabilizer HuR, and C/EBP-beta, a transcription factor for COX-2. All markers showed a statistically significant difference between early-onset gastric cancers and conventional gastric cancers, using a chi2 test. In particular, early-onset gastric cancers displayed a COX-2 Low, TFF1-expressing phenotype, whereas COX-2 overexpression and loss of TFF1 was found in conventional cancers, and this difference between early-onset gastric cancers and conventional cancers remained statistically significant when adjusted for location and histology (P<0.0001 and P = 0.002 respectively). We found that COX-2 overexpression correlates significantly with loss of TFF1 (P = 0.001), overexpression of C/EBP-beta (P<0.001) and cytoplasmic HuR (P = 0.016). COX-2 was significantly associated with p53 positivity (P = 0.003). Abnormalities in E-Cadherin correlated significantly with diffuse phenotype, whereas high expression of COX-2, loss of TFF1 and overexpression of C/EBP-beta correlated with the intestinal phenotype. Our results provide further evidence that early-onset gastric cancer exhibits a distinctive expression profile that may have practical implications.
许多研究探讨了胃癌的分子遗传学，但专门针对年轻患者的研究较少，且没有对早发性胃癌（≤45岁）和传统胃癌之间的分子表达进行比较。与非肿瘤性黏膜相比，环氧化酶-2（COX-2）在胃腺癌中的表达升高，鉴于有研究表明非甾体抗炎药使用者患胃癌的风险降低，我们选择使用组织微阵列研究113例早发性胃癌中COX-2及相关分子的表达，并将其与91例传统胃癌进行比较。这些标志物包括已知在传统胃癌发生过程中起重要作用的分子，如E-钙黏蛋白、p53、COX-2、三叶因子-1（TFF1）、β-连环蛋白、p16和c-myc；以及尚未被描述为在胃癌中起重要作用的分子，如转录因子c-jun、COX-2 mRNA稳定剂HuR和COX-2的转录因子C/EBP-β。使用卡方检验，所有标志物在早发性胃癌和传统胃癌之间均显示出统计学上的显著差异。特别是，早发性胃癌表现出COX-2低表达、TFF1表达的表型，而在传统癌症中发现COX-2过表达和TFF1缺失，并且在调整部位和组织学后，早发性胃癌与传统癌症之间的这种差异仍具有统计学意义（分别为P<0.0001和P = 0.002）。我们发现COX-2过表达与TFF1缺失（P = 0.001）、C/EBP-β过表达（P<0.001）和细胞质HuR（P = 0.016）显著相关。COX-与p53阳性显著相关（P = 0.003）。E-钙黏蛋白异常与弥漫性表型显著相关，而COX-2高表达、TFF1缺失和C/EBP-β过表达与肠型表型相关。我们的结果提供了进一步的证据，表明早发性胃癌表现出独特的表达谱，可能具有实际意义。
