Institute of Molecular Pathology and Immunology of the University of Porto, Portugal.
Int J Cancer. 2011 Apr 1;128(7):1606-13. doi: 10.1002/ijc.25495. Epub 2010 Jun 7.
Microsatellite instability (MSI) is a major pathway involved in gastric carcinogenesis occurring in 20% of gastric cancer (GC). However, it is not clear whether MSI phenotype preferentially occurs in the sporadic or familial GC, when stringent inclusion criteria are used. The aim of this study was to compare the frequency of MSI and hypermethylation of MLH1 promoter in a large series of familial GC patients (non-HNPCC and non-CDH1-related) and sporadic cases. Additionally, we analysed the immunoexpression of MMR proteins in a fraction of cases. Overall, the frequency of familial GC was 7.1%, and the frequency of hereditary tumours was 4.6%. MSI phenotype and MLH1 hypermethylation frequencies were not statistical different between familial and sporadic GC settings. Further, the MSI phenotype was not associated with any clinico-pathological features studied in the familial GC setting, whereas in the sporadic setting, it was associated with older age, female gender and intestinal histotype. Using our stringent Amsterdam-based clinical criteria to select familial GC (number of cases, age of onset), we verified that sporadic and familial cases differed in gender but shared histopathological features. We verified that the frequency of MSI was similar in familial and sporadic GC settings, demonstrating that this molecular phenotype is not a hallmark of familial GC in contrast to what is verified in HNPCC. Moreover, we observed that the frequency of MLH1 hypermethylation is similar in sporadic and familial cases suggesting that in both settings MSI is not associated to MMR genetic alterations but in contrast to epigenetic deregulation.
微卫星不稳定性 (MSI) 是参与发生在 20%胃癌 (GC) 中的胃癌发生的主要途径。然而，当使用严格的纳入标准时，MSI 表型是否优先发生在散发性或家族性 GC 中尚不清楚。本研究的目的是比较大量家族性 GC 患者（非 HNPCC 和非 CDH1 相关）和散发性病例中 MSI 和 MLH1 启动子高甲基化的频率。此外，我们分析了一部分病例中 MMR 蛋白的免疫表达。总体而言，家族性 GC 的频率为 7.1%，遗传性肿瘤的频率为 4.6%。MSI 表型和 MLH1 高甲基化频率在家族性和散发性 GC 之间无统计学差异。此外，MSI 表型与家族性 GC 研究中的任何临床病理特征均无关，而在散发性 GC 中，它与年龄较大、女性和肠型有关。使用我们基于阿姆斯特丹的严格临床标准来选择家族性 GC（病例数量、发病年龄），我们验证了在性别方面，散发性和家族性病例存在差异，但具有相似的组织病理学特征。我们验证了 MSI 在家族性和散发性 GC 中的频率相似，表明与 HNPCC 中验证的情况相反，这种分子表型不是家族性 GC 的标志。此外，我们观察到 MLH1 高甲基化在散发性和家族性病例中的频率相似，表明在这两种情况下，MSI 均与 MMR 基因改变无关，而是与表观遗传失调相反。
