Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer.
Genomic Landscape of Somatic Alterations in Esophageal Squamous Cell Carcinoma and Gastric Cancer.
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DOI：
10.1158/0008-5472.can-15-0338
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发表时间：
2016-04-01
期刊：
影响因子：
11.2
通讯作者：
Lee MP
中科院分区：
文献类型：
--
作者：
Hu N;Kadota M;Liu H;Abnet CC;Su H;Wu H;Freedman ND;Yang HH;Wang C;Yan C;Wang L;Gere S;Hutchinson A;Song G;Wang Y;Ding T;Qiao YL;Koshiol J;Dawsey SM;Giffen C;Goldstein AM;Taylor PR;Lee MP
胃癌和食道癌是全球癌症死亡的第二和第六大原因。胃癌和食管鳞状细胞癌（ESCC）的多种基因组改变已被识别，但基因组结构变异和突变的全谱尚未被发现。在此，我们报告了 15 名患者的 30 个肿瘤和血液样本的全基因组测序结果，其中 4 名患者患有 ESCC，7 名患者患有胃贲门腺癌 (GCA)，4 名患者患有胃非贲门腺癌 (GNCA)。分析显示，GCA 中 A>C 突变很常见，除了先前研究中指出的 A 优先核苷酸序列位于突变的 5 个素数之外，我们还发现 T 在 5 个素数碱基中富集。 GCA 中的 A>C 突变表明鸟嘌呤氧化可能是癌症诱变的潜在机制。此外，我们还鉴定了胃癌和食管癌中存在突变的基因，包括众所周知的癌症基因TP53、JAK3、BRCA2、FGF2、FBXW7、MSH3、PTCH、NF1、ERBB2和CHEK2，以及潜在的新型癌症相关基因KISS1R、AMH、MNX1、WNK2和PRKRIR。最后，我们在至少 30% 的肿瘤基因中发现了反复出现的染色体改变，包括 MACROD2、FHIT 和 PARK2，这些基因通常是基因内缺失。这些结构改变使用 TCGA 数据集进行了验证。我们的研究为了解胃癌和食管鳞癌发展背后的基因组景观、基因组不稳定性和突变谱提供了新的见解。
Gastric cancer and esophageal cancer are the 2nd and 6th leading causes of cancer death worldwide. Multiple genomic alterations underlying gastric cancer and esophageal squamous cell carcinoma (ESCC) have been identified, but the full spectrum of genomic structural variations and mutations have yet to be uncovered. Here we report the results of whole genome sequencing of 30 samples comprising tumor and blood from 15 patients, four of whom presented with ESCC, seven with gastric cardia adenocarcinoma (GCA), and four with gastric noncardia adenocarcinoma (GNCA). Analyses revealed that an A>C mutation was common in GCA, and in addition to the preferential nucleotide sequence of A located 5 prime to the mutation as noted in previous studies, we found enrichment of T in the 5 prime base. The A>C mutations in GCA suggested that oxidation of guanine may be a potential mechanism underlying cancer mutagenesis. Furthermore, we identified genes with mutations in gastric cancer and ESCC, including well-known cancer genes, TP53, JAK3, BRCA2, FGF2, FBXW7, MSH3, PTCH, NF1, ERBB2, and CHEK2, and potentially novel cancer-associated genes, KISS1R, AMH, MNX1, WNK2, and PRKRIR. Finally, we identified recurrent chromosome alterations in at least 30% of tumors in genes including MACROD2, FHIT, and PARK2 that were often intragenic deletions. These structural alterations were validated using the TCGA dataset. Our studies provide new insights into understanding the genomic landscape, genome instability, and mutation profile underlying gastric cancer and ESCC development.