Genomic Landscape of Endometrial, Ovarian, and Cervical Cancers in Japan from the Database in the Center for Cancer Genomics and Advanced Therapeutics

Abstract

This study aimed to comprehensively clarify the genomic landscape and its association with tumor mutational burden-high (TMB-H, ≥10 mut/Mb) and microsatellite instability-high (MSI-H) in endometrial, cervical, and ovarian cancers. We obtained genomic datasets of a comprehensive genomic profiling test, FoundationOne® CDx, with clinical information using the “Center for Cancer Genomics and Advanced Therapeutics” (C-CAT) database in Japan. Patients can undergo the tests only after standardized treatments under universal health insurance coverage. Endometrial cancers were characterized by a high frequency of TMB-H and MSI-H, especially in endometrioid carcinomas. The lower ratio of POLE exonuclease mutations and the higher ratio of TP53 mutations compared to previous reports suggested the prognostic effects of the molecular subtypes. Among the 839 cervical cancer samples, frequent mutations of KRAS, TP53, PIK3CA, STK11, CDKN2A, and ERBB2 were observed in adenocarcinomas, whereas the ratio of TMB-H was significantly higher in squamous cell carcinomas. Among the 1606 ovarian cancer samples, genomic profiling of serous, clear cell, endometrioid, and mucinous carcinomas was characterized. Pathogenic mutations in the POLE exonuclease domain were associated with high TMB, and the mutation ratio was low in both cervical and ovarian cancers. The C-CAT database is useful for determining the mutational landscape of each cancer type and histological subtype. As the dataset is exclusively collected from patients after the standardized treatments, the information on “druggable” alterations highlights the unmet needs for drug development in major gynecological cancers.

Emerging Advances in Endometrial Cancer: Integration of Molecular Classification into Staging for Enhanced Prognostic Accuracy and Implications for Racial Disparities

“…The most common mutations affect the PTEN gene, but mutations in other genes like PIK3CA, KRAS, and ARID1A are also frequently observed [ 47 ]. Of particular importance is the PI3K pathway, known to play an important role in genomic stability, cell cycle regulation and cell survival, resistance to chemotherapy, and DNA replication [ 48 ]. Inhibition of this pathway may lead to genomic instability and mitotic catastrophe [ 48 ].…”

“…Of particular importance is the PI3K pathway, known to play an important role in genomic stability, cell cycle regulation and cell survival, resistance to chemotherapy, and DNA replication [ 48 ]. Inhibition of this pathway may lead to genomic instability and mitotic catastrophe [ 48 ].…”