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.