Guerra Joana, Pinto Carla, Pinto Pedro, Pinheiro Manuela, Santos Catarina, Peixoto Ana, Escudeiro Carla, Barbosa Ana, Porto Miguel, Francisco Inês, Lopes Paula, Isidoro Ana Raquel, Cunha Ana Luísa, Albuquerque Cristina, Claro Isabel, Oliveira Carla, Silva João, Teixeira Manuel R
Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal.
Doctoral Programme in Biomedical Sciences, School Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal.
Cancers (Basel). 2023 Aug 29;15(17):4313. doi: 10.3390/cancers15174313.
The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the gene, and more rarely in the gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of and germline variants to HDGC. Additionally, we also intended to compare the frequencies of and (and eventually ) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the gene in 67 cases affected with early-onset/familial mixed gastric carcinomas and the and genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for pathogenic germline variants. A deleterious germline variant was found in 0.7% (1/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of deleterious variants found by us in this setting. No deleterious variants were found in , but six variants of uncertain significance were identified in this gene. We did not find any pathogenic , or variant in index patients with early-onset/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the gene in inherited gastric cancer predisposition is still unclear.
最具特征的遗传性胃癌形式是遗传性弥漫性胃癌（HDGC），这是一种常染色体显性综合征，其特征是弥漫性胃癌和小叶性乳腺癌的发病风险增加。HDGC主要由该基因中的种系致病变异引起，较少由该基因中的变异引起。此外，国际胃癌连锁联盟（IGCLC）指南并未阐明在HDGC基因检测标准中是否应考虑混合性胃癌（伴有弥漫性成分）。我们旨在评估和种系变异对HDGC的贡献。此外，我们还打算比较弥漫性和混合性胃癌患者之间和（最终）种系变异的频率，以评估对于后者患者是否应考虑对这些基因进行基因检测。我们分析了67例早发性/家族性混合性胃癌患者的基因，以及208例弥漫性或混合性胃癌且种系致病变异检测呈阴性患者的和基因。在符合2020年IGCLC标准的弥漫性胃癌患者中，0.7%（1/141）发现有害的种系变异，而我们在此情况下发现的有害变异率为2.8%。基因中未发现有害变异，但在该基因中鉴定出六个意义未明的变异。在早发性/家族性混合性胃癌的索引患者中，我们未发现任何致病性、或变异，因此没有证据支持将这种肿瘤类型纳入这些基因种系变异的检测标准。基因在遗传性胃癌易感性中的作用仍不清楚。
