An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer
An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer
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DOI：
10.1002/path.4152
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发表时间：
2013-03-01
影响因子：
7.3
通讯作者：
Bernards, Rene
中科院分区：
文献类型：
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作者：
Majewski, Ian J.;Kluijt, Irma;Bernards, Rene
弥漫性胃癌通常表现为晚期肿瘤，因此5年生存率很低。一些胃癌是遗传性的，这些往往是弥漫型的; 30 - 40%的遗传性弥漫性胃癌（HDGC）可以解释为E-钙粘蛋白（CDH 1）的缺陷种系等位基因，但对于其余的家庭，驱动易感性的因素仍然未知。我们获得了一个大的HDGC家系，在CDH 1没有明显的突变，并应用外显子组测序，以确定新的基因参与胃癌。我们确定了一个生殖系截短等位基因的-E-连环蛋白（CTNNA 1），这是目前在两个家庭成员与浸润性弥漫性胃癌和四个粘膜内印戒细胞检测作为内镜监测的一部分。其余的CTNNA 1等位基因在可用于筛查的家族中的两个弥漫性胃癌中被沉默，这对于在内窥镜活检中鉴定的印戒细胞也是如此。由于-E-连环蛋白的功能在同一个复杂的E-钙粘蛋白，我们的研究结果呼吁注意更广泛的信号网络周围的这些蛋白质在HDGC。我们还在一个肿瘤中检测到体细胞突变，并发现与散发性胃癌中突变的基因有大量重叠，包括PIK 3CA，ARID 1A，MED 12和MED 23。
Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type; 3040% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of -E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since -E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.