Buffart T E, Overmeer R M, Steenbergen R D M, Tijssen M, van Grieken N C T, Snijders P J F, Grabsch H I, van de Velde C J H, Carvalho B, Meijer G A
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Br J Cancer. 2008 Dec 2;99(11):1802-7. doi: 10.1038/sj.bjc.6604777. Epub 2008 Nov 11.
T-lymphocyte maturation associated protein, MAL, has been described as a tumour-suppressor gene with diagnostic value in colorectal and oesophageal cancers, and can be inactivated by promoter hypermethylation. The aim of this study was to analyse the prevalence of MAL promoter hypermethylation and the association with mRNA expression in gastric cancers and to correlate methylation status to clinicopathological data. Bisulphite-treated DNA isolated from formalin-fixed and paraffin-embedded samples of 202 gastric adenocarcinomas and 22 normal gastric mucosae was subjected to real-time methylation-specific PCR (Q-MSP). Two regions within the MAL promoter (M1 and M2) were analysed. In addition, 17 frozen gastric carcinomas and two gastric cancer cell lines were analysed both by Q-MSP and real-time RT-PCR. Methylation of M1 and M2 occurred in 71 and 80% of the gastric cancers, respectively, but not in normal gastric mucosa tissue. Hypermethylation of M2, but not M1, correlated with significantly better disease-free survival in a univariate (P=0.03) and multivariate analysis (P=0.03) and with downregulation of expression (P=0.01). These results indicate that MAL has a putative tumour-suppressor gene function in gastric cancer, and detection of promoter hypermethylation may be useful as a prognostic marker.
T淋巴细胞成熟相关蛋白（MAL）已被描述为一种在结直肠癌和食管癌中具有诊断价值的肿瘤抑制基因，且可因启动子高甲基化而失活。本研究旨在分析MAL启动子高甲基化在胃癌中的发生率及其与mRNA表达的关系，并将甲基化状态与临床病理数据相关联。从202例胃腺癌和22例正常胃黏膜的福尔马林固定石蜡包埋样本中提取经亚硫酸氢盐处理的DNA，进行实时甲基化特异性PCR（Q-MSP）。分析了MAL启动子内的两个区域（M1和M2）。此外，对17例冷冻胃癌和两个胃癌细胞系进行了Q-MSP和实时逆转录PCR分析。M1和M2的甲基化分别发生在71%和80%的胃癌中，但在正常胃黏膜组织中未发生。M2而非M1的高甲基化在单因素分析（P=0.03）和多因素分析（P=0.03）中与显著更好的无病生存率相关，且与表达下调相关（P=0.01）。这些结果表明，MAL在胃癌中具有假定的肿瘤抑制基因功能，并提示启动子高甲基化检测可能作为一种预后标志物。
