Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Mod Pathol. 2021 Mar;34(3):637-646. doi: 10.1038/s41379-020-0614-0. Epub 2020 Jul 8.
Gastric-type mucinous carcinoma (GAS) is a recently established variant of endocervical mucinous adenocarcinoma that is characterized as being unrelated to HPV and having aggressive behavior and chemoresistance. GAS has a distinct morphology resembling nonneoplastic gastric glands or pancreaticobiliary adenocarcinoma, and their possible genetic similarity has been posed. In this study, next-generation sequencing was performed in 21 GAS cases using a customized panel including 94 cancer-associated genes. A total of 54 nonsynonymous somatic mutations were detected with an average mutation rate of 2.6 per lesion (range: 0-9). The most frequently mutated gene was TP53 (11/21, 52.4%), followed by STK11, HLA-B, PTPRS (4/21, 19.0%), FGFR4 (3/21, 14.3%), GNAS, BRCA2, ELF3, ERBB3, KMT2D, SLX4 (2/21, 9.5%), CDH1, EPCAM, KRAS, MLH1, RNF43, SNAI1, TWIST1, ZEB1, ZEB2, and so on (1/21, 4.8%). The mutated genes were mostly involved in signal transduction, DNA damage repair, and epithelial-mesenchymal transition (EMT). Correlation of TP53 mutation and p53 protein expression demonstrated that 31.3% with abnormal p53 expression harbored wild-type TP53. Compared to genetic features of gastric and pancreaticobiliary adenocarcinoma, TP53 mutations were frequent in both GAS and gastrointestinal adenocarcinoma. While KMT2D, ERBB3, and RNF43 mutations were shared between GAS and gastric adenocarcinoma, highly mutated genes in pancreatic ductal adenocarcinoma such as KRAS, SMAD4, and CDKN2A were rarely mutated in GAS. Of frequently mutated genes in cholangiocarcinoma, BAP1 and HLA-B were identified in GAS. Frequent EMT-related gene mutations suggested a possible role of EMT-related pathways in tumor dissemination and chemoresistance of GAS. In addition, GAS shared some genetic features with gastrointestinal adenocarcinoma. These findings provide a clue in understanding the biological basis of GAS.
胃型黏液性癌（GAS）是一种新近确立的宫颈黏液性腺癌变异型，其特征为与 HPV 无关，且具有侵袭性和化疗耐药性。GAS 的形态学表现独特，类似于非肿瘤性胃腺体或胰腺胆管腺癌，并且它们可能具有遗传相似性。在这项研究中，使用包括 94 个癌症相关基因的定制面板对 21 例 GAS 病例进行了下一代测序。共检测到 54 个非同义体细胞突变，平均每个病变 2.6 个突变（范围：0-9）。突变频率最高的基因是 TP53（21 例中有 11 例，52.4%），其次是 STK11、HLA-B、PTPRS（21 例中有 4 例，19.0%）、FGFR4（21 例中有 3 例，14.3%）、GNAS、BRCA2、ELF3、ERBB3、KMT2D、SLX4（21 例中有 2 例，9.5%）、CDH1、EPCAM、KRAS、MLH1、RNF43、SNAI1、TWIST1、ZEB1、ZEB2 等（21 例中有 1 例，4.8%）。突变基因主要涉及信号转导、DNA 损伤修复和上皮-间充质转化（EMT）。TP53 突变与 p53 蛋白表达的相关性表明，异常表达的 p53 中有 31.3%为野生型 TP53。与胃和胰腺胆管腺癌的遗传特征相比，GAS 和胃肠道腺癌中 TP53 突变均较频繁。虽然 KMT2D、ERBB3 和 RNF43 突变在 GAS 和胃腺癌中共享，但胰腺导管腺癌中高度突变的基因如 KRAS、SMAD4 和 CDKN2A 在 GAS 中很少发生突变。在胆管癌中经常发生突变的基因中，BAP1 和 HLA-B 在 GAS 中被鉴定出来。频繁的 EMT 相关基因突变更提示 EMT 相关途径可能在 GAS 的肿瘤播散和化疗耐药中发挥作用。此外，GAS 与胃肠道腺癌具有一些遗传特征。这些发现为理解 GAS 的生物学基础提供了线索。
