Transcriptome profiling of gastric-type endocervical adenocarcinomas identifies key signaling pathways for tumor progression.

ABSTRACT

OBJECTIVE: Gastric-type endocervical carcinoma is a rare entity of carcinoma of the cervix. In contrast to the intestinal type, the gastric type is not related to Human Papilloma Virus (HPV) infection and has been reported to be much more aggressive than the usual type. Oncogenic pathways involved in this poor-prognosis phenotype are largely unexplored. METHODS: We compared activation of the main signaling pathways involved in cancer progression between the intestinal- (n = 5), gastric- (n = 6) and usual-type (n = 6) adenocarcinomas of the cervix using a targeted transcriptomic approach (expression of 770 genes) on FFPE samples. RESULTS: We identified a gene-expression signature composed of 11 genes that allows the classification of these endocervical carcinoma as three distinct molecular entities. There were similarities between mucinous endocervical carcinomas (gastric and intestinal types) despite difference in pathogenesis related to HPV infection. Among HPV-related endocervical carcinoma, the intestinal type could be molecularly distinguished from the usual type by high expression of EIF2AK3 and low expression of PPFIBP2 genes, supporting its classification as a distinct entity. Overexpression of TAL1 and S1PR1 genes were characteristic of the gastric type. The usual type was characterized by high expression of occludin and VAV3 genes. Tight junction disruptions might play an essential role in the metastatic potential of mucinous endocervical carcinoma with concomitant loss of OCLN and claudin 4 proteins. An overexpression of NTRK1 transcript was observed in mucinous endocervical carcinomas when compared to the usual type. CONCLUSIONS: This transcriptomic study identified a signature that supports the classification of endocervical carcinomas as three distinct entities usual-, intestinal- and gastric-type. It also points out to disruption of tight junctions as a potential mechanism of metastatic dissemination of these rare tumors.