胃腺癌中的 APC 突变模式富含与生存率降低相关的错义变异。,Genes, Chromosomes and Cancer

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胃腺癌中的 APC 突变模式富含与生存率降低相关的错义变异。
Genes, Chromosomes and Cancer Pub Date : 2019-08-10 , DOI: 10.1002/gcc.22792
Jill C Rubinstein ₁ , Sajid A Khan ₂ , Emily R Christison-Lagay ₂ , Charles Cha ₂

Affiliation

腺瘤性结肠息肉病 (APC) 突变与家族性腺瘤性息肉病 (FAP) 有因果关系，并且是包括胃腺癌在内的多种肿瘤类型的复发性躯体事件。FAP 疾病的严重程度与特定的 APC 突变相关，但特定突变对胃癌表型的影响尚未得到充分研究。来自 Genomic Data Commons (GDC) 的测序数据表明，胃癌中的 APC 突变模式与结肠癌中的突变模式截然不同。使用 MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow 对来自 GDC 中 APC 突变结肠癌和胃腺癌的外显子组测序数据进行单核苷酸变异 (SNV) 过滤。在 57/441 个胃癌 (12.9%) 和 309/433 个结肠腺癌 (71.4%) 中发现了 APC 突变。肿瘤类型之间的停止、移码和错义突变的比例存在显着差异 (P < .00001)。结肠肿瘤以移码和止损为主，分别占 47.7% 和 35.7%。相比之下，47.1% 的胃突变是错义的。与其他突变亚型相比，具有错义突变的胃肿瘤显示总体生存率降低 (P = .008)。在胃样本中，25.9% 的移码突变和终止突变位于基因的 3' 部分，而结肠样本的这一比例为 1.4%。APC 突变在胃癌和结肠腺癌中表现出不同的分布，在胃肿瘤中向错义变异转变，并且在包含它们的胃肿瘤中存活率更差。

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APC mutational patterns in gastric adenocarcinoma are enriched for missense variants with associated decreased survival.

Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with specific APC mutations, but the impact of given mutations on phenotype in gastric cancer is not well studied. Sequencing data from the Genomic Data Commons (GDC) demonstrate an APC mutational pattern in gastric cancer that differs dramatically from that seen in colon cancer. Exome sequencing data from APC-mutant colon and gastric adenocarcinomas in GDC was filtered for single nucleotide variants (SNVs) using MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow. APC mutations were found in 57/441 gastric (12.9%) and 309/433 colon adenocarcinomas (71.4%). There was a significant difference in the proportion of stopgain, frameshift, and missense mutations between tumor types(P < .00001). Colon tumors were predominated by frameshift and stopgains, comprising 47.7% and 35.7%, respectively. In contrast, 47.1% of gastric mutations were missense. Gastric tumors harboring missense mutations showed decreased overall survival relative to other mutational subtypes(P = .008). In the gastric samples, 25.9% of frameshift and stopgain mutations are in the 3' portion of the gene, compared to 1.4% of colon samples. APC mutations demonstrate different distributions in gastric and colon adenocarcinoma, with a shift toward missense variants in gastric tumors and worse survival in gastric tumors harboring them. As different mutations confer variable degrees of protein dysfunction and resultant clinical manifestation, expanded investigation of specific mutational patterns will prove integral to future-risk stratification strategies.

更新日期：2019-11-01

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