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

backgroundSynchronous 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.

methodsWhole-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.

resultsGermline 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.

conclusionsSMMN-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.