Academic Laboratory of Medical Genetics, University of Cambridge, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
Familial Gastric Cancer Study, Department of Oncology, University of Cambridge, Cambridge, UK.
Lancet Gastroenterol Hepatol. 2018 Jul;3(7):489-498. doi: 10.1016/S2468-1253(18)30079-7. Epub 2018 Apr 27.
Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.
We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.
Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.
The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.
UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.
E-钙黏蛋白基因（CDH1）中的种系致病性变异与遗传性弥漫性胃癌的发生密切相关。对于不携带 CDH1 致病性变异的遗传性弥漫性胃癌患者的家族，缺乏指导风险评估和管理的相关数据，这使得在进行监测和降低风险手术方面难以做出明智的决策。本研究旨在鉴定与不携带致病性 CDH1 变异的遗传性弥漫性胃癌患者家族易感性相关的新候选基因。
我们对 22 个不携带致病性 CDH1 变异的家族中 39 名个体（28 名遗传性弥漫性胃癌患者和 11 名无病一级亲属）的血液进行全外显子组测序。使用基因相互作用分析对具有功能丧失变异的基因进行优先级排序，以鉴定可能与遗传性弥漫性胃癌易感性相关的基因簇。
在 6 个遗传性弥漫性胃癌患者家族的先证者中发现了与蛋白相关的种系变异；这些变异存在于已知易患癌症的基因和研究较少的 DNA 修复基因中。一个有胃癌和乳腺癌病史的家族中发现了 PALB2 基因的框移缺失。两个无关联的受累个体中发现了两个不同的 MSH2 变异，包括一个框移插入和一个先前描述的起始密码子缺失。一个家族的 DNA 修复基因 ATR 和 NBN 具有独特的变异组合。两个 RECQL5 基因的变异在两个无关联的家族中被发现：一个错义变异和一个剪接受体变异。
本研究结果提示已知的癌症易感性基因 PALB2 在不携带致病性 CDH1 变异的遗传性弥漫性胃癌患者家族中起作用。我们还鉴定了这些家族中与疾病风险相关的新候选基因。
英国医学研究理事会（萨克勒计划）、欧盟第七框架计划下的欧洲研究理事会（2007-13 年）、英国国家健康研究所剑桥生物医学研究中心、实验癌症医学中心和英国癌症研究中心。
