Genetic characteristics of gastric-type mucinous carcinoma of the uterine cervix

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 wasTP53(11/21, 52.4%), followed bySTK11,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 ofTP53mutation and p53 protein expression demonstrated that 31.3% with abnormal p53 expression harbored wild-typeTP53. Compared to genetic features of gastric and pancreaticobiliary adenocarcinoma,TP53mutations were frequent in both GAS and gastrointestinal adenocarcinoma. WhileKMT2D, ERBB3, andRNF43mutations were shared between GAS and gastric adenocarcinoma, highly mutated genes in pancreatic ductal adenocarcinoma such asKRAS,SMAD4, andCDKN2Awere rarely mutated in GAS. Of frequently mutated genes in cholangiocarcinoma,BAP1andHLA-Bwere 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.