TP53 gene and pathway alterations in gastric-type adenocarcinoma of the cervix.

Human papillomavirus (HPV) infection contributes to the development of almost all cervical malignancies, aside from gastric-type adenocarcinoma of the cervix (GAS), a rare aggressive subtype without HPV infection. To address the carcinogenic mechanism of this disease, we performed a comparative multi-omics analysis of GAS and usual-type endocervical adenocarcinoma (UEA) in three independent cohorts of patients with GAS and UEA. The first cohort comprised eight GAS and 22 UEA patients treated at the National Cancer Center Hospital between 2002 and 2020, who were examined by targeted and whole transcriptome sequencing. The other two cohorts comprised 52 GAS and 109 UEA patients and 39 GAS and 232 UEA patients, whose mutational data were obtained from the C-CAT (Japanese patients) and GENIE (US patients) public databases, respectively. Metabolomic analysis was performed in eight patients, including five with GAS. TP53 mutations were more prevalent in GAS than in UEA in all three cohorts. Transcriptome analysis consistently revealed frequent suppression of TP53-related pathways in GAS. Metabolites preferentially detected in GAS tissues suggest TP53 alterations are implicated in intratumoral metabolic properties. The development of GAS is likely driven by TP53 mutations, which play a large role in shaping intracellular signaling and metabolic profiles within tumor cells.