Oliveira Carla, Ferreira Paulo, Nabais Sérgio, Campos Luisa, Ferreira Ana, Cirnes Luís, Alves Catarina Castro, Veiga Isabel, Fragoso Maria, Regateiro Fernando, Dias Luis Moreira, Moreira Herculano, Suriano Gianpaolo, Machado José Carlos, Lopes Carlos, Castedo Sérgio, Carneiro Fátima, Seruca Raquel
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Roberto Frias, s/n, 4200-465 Porto, Portugal.
Eur J Cancer. 2004 Aug;40(12):1897-903. doi: 10.1016/j.ejca.2004.04.027.
Approximately 30% of all hereditary diffuse gastric cancer (HDGC) families carry CDH1 germline mutations. The other two thirds remain genetically unexplained and are probably caused by alterations in other genes. Using polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP)/sequencing, we screened 32 Portuguese families with a history of gastric cancer and 23 patients with early onset gastric cancer for CDH1 germline mutations. In probands negative for CDH1 mutations, we screened genes involved in hereditary cancer syndromes in which gastric cancer may be one of the component tumours, namely p53 (Li-Fraumeni Syndrome) and hMLH1 and hMSH2 (HNPCC). We also screened in these patients for mutations in Caspase-10, a gene inactivated in sporadic gastric cancer, and SMAD4, a gene whose inactivation in mice is associated with signet-ring cell carcinoma of the stomach. One of the families fulfilling the HDGC criteria harboured a CDH1 germline mutation, and one of the families with incomplete criteria harboured a p53 germline mutation. No mutations were identified in hMLH1 and hMSH2, and only sequence variants were found in SMAD4 and Caspase-10. The present work reports for the first time CDH1 germline mutations in Portuguese gastric cancer families, and highlights the need for p53 mutation screening in families lacking CDH1 germline mutations, in a country with one of the highest incidences of gastric cancer in the world. No evidence was found for a role of germline mutations in SMAD4 and Caspase-10 in families lacking CDH1 mutations.
在所有遗传性弥漫性胃癌（HDGC）家族中，约30%携带CDH1种系突变。另外三分之二则仍无法从基因角度解释，可能是由其他基因的改变所致。我们采用聚合酶链反应（PCR）/单链构象多态性（SSCP）/测序技术，对32个有胃癌家族史的葡萄牙家族以及23例早发性胃癌患者进行了CDH1种系突变筛查。在CDH1突变检测呈阴性的先证者中，我们筛查了可能以胃癌作为组成肿瘤之一的遗传性癌症综合征相关基因，即p53（李-佛美尼综合征）以及hMLH1和hMSH2（遗传性非息肉病性结直肠癌）。我们还在这些患者中筛查了Caspase-10（一种在散发性胃癌中失活的基因）和SMAD4（一种在小鼠中失活与胃印戒细胞癌相关的基因）的突变情况。一个符合HDGC标准的家族携带CDH1种系突变，一个不符合标准的家族携带p53种系突变。未在hMLH1和hMSH2中鉴定出突变，仅在SMAD4和Caspase-10中发现了序列变异。本研究首次报道了葡萄牙胃癌家族中的CDH1种系突变，并强调了在一个胃癌发病率位居世界前列的国家，对于缺乏CDH1种系突变的家族进行p53突变筛查的必要性。未发现缺乏CDH1突变的家族中，SMAD4和Caspase-10种系突变发挥作用的证据。
