Alterations in the Tp53 Gene and Associated Pathway Drive Development Og a Gastric-Type Adenocarcinoma Rather than the Usual-Type Endocervical Adenocarcinoma

Abstract

Background: 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).Methods: This study analyzed three independent cohorts of patients with GAS and UEA. The first cohort comprised 8 GAS and 22 UEA patients treated at the NCCH between 2002 and 2020, who were examined by targeted and RNA 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.Results: TP53 mutations were more prevalent in GAS than in UEA in all three cohorts. Transcriptome analysis consistently revealed the frequent suppression of TP53-related pathways in GAS. Metabolites preferentially detected in GAS tissues suggest TP53 alterations are implicated in intratumoral metabolic properties.Conclusions: Development of GAS is dependent on alterations in TP53, which underlies the properties of intracellular signaling and metabolomics in tumor cells.

Note:
Funding Declaration: This work was supported by a Grant-in-Aid for Young Scientists (B) Number 20K18207 a Grant-in-Aid for Scientific Research (C) Number 20K09636, 19K16572 and 22K09563, a Grant-in-Aid for Scientific Research (B) Number 20H03695, BRIDGE (programs for bridging the gap between R&D and the ideal society (Society 5.0)), and the National Cancer Center Research and Development Fund (2023-J-2, NCC Biobank, and NCC Core Facility).

Conflict of Interests: None.

Ethical Approval: The study protocol was approved by the Institutional Review Board (IRB) of the National Cancer Center (NCC) (approval number 2017-136), and all patients provided written informed consent. This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki. C-CAT data were accessed through the C-CAT Research-Use Portal site after obtaining approval from the NCC-IRB (approval number 2020-067) and the C-CAT Data Utilization Review Board (approval number CDU2021-001N).

Keywords: cervical cancer, Next-Generation Sequencing, Transcriptome, Metabolome analysis, HPV-independent, TP53 mutation