Germline predisposition and somatic mutational landscape in synchronous mucinous metaplasia and neoplasia of the female genital tract.

Authors

Ying Yuan, Li Zhang, Jiongbo Liao, Bo Wang, Linghui Lu, Dongchen Chu, Yue Shi, Jiaqi Liu, Feng Zhang, Shuyan Tang, Chao Wang

Published in

Clinical and translational medicine. Volume 16. Issue 8. Pages e70768.

Abstract

Synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT) with gastric-type differentiation is a rare disorder with genetic predisposition. Pathogenic STK11 variants explain only a minority of reported cases, suggesting additional susceptibility genes. However, the genetic landscape of SMMN-FGT remains poorly characterised.
Whole-exome sequencing was performed on 19 lesions and matched normal tissues from 13 cases with SMMN-FGT. Pathogenic germline variants in cancer-predisposition genes were identified, and their carrier frequencies were compared with those in common gynaecologic cancers. The somatic mutational landscape of SMMN-FGT was characterised and compared with conventional cervical cancers. Clonal analyses were performed to identify candidate driver genes, and the functional effects of KDM5C were evaluated in vitro using siRNA-mediated knockdown and plasmid-mediated overexpression assays.
Germline analysis showed a markedly higher prevalence of pathogenic variants in cancer-associated genes in SMMN-FGT (38.5%) than common gynaecologic cancers (4.4%-8.6%). Two cases carried pathogenic BRCA1 variants, raising the possibility that SMMN-FGT may be part of a broader BRCA1-associated phenotypic spectrum. Somatic profiling identified TP53 mutations in five (26.3%) of 19 total lesions, four (80.0%) of which were malignant. Gastric-type cervical adenocarcinoma (GCA) was the most common malignant subtype of SMMN-FGT, with TP53 mutations detected in three (42.9%) of seven GCA lesions and no PIK3CA mutations. By contrast, conventional cervical cancers frequently harbour PIK3CA mutations (27%-41%), whereas TP53 mutations are relatively uncommon. Clonal analysis identified KDM5C as a candidate driver. KDM5C overexpression reduced cell viability, migration and invasion and increased apoptosis, whereas its knockdown produced the opposite effects.
SMMN-FGT has a distinct genetic profile characterised by an enrichment of pathogenic germline variants, and recurrent TP53 mutations predominantly affecting malignant lesions. KDM5C may function as a candidate tumour suppressor. These findings advance our understanding of SMMN-FGT pathogenesis and warrant further investigation of its diagnostic and therapeutic implications. Key Points SMMN-FGT exhibits a distinct landscape of germline cancer-predisposition variants. TP53 mutations are associated with malignant progression in SMMN-FGT. KDM5C is identified as a potential tumour suppressor in SMMN-FGT.

PMID:
42605498
Bibliographic data and abstract were imported from PubMed on 17 Aug 2026.

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