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

Heterogeneous germline predisposition: pathogenic STK11 variants account for only a minority of cases, and exome sequencing reveals additional predisposition genes including BRCA1; malignant progression is accompanied by somatic TP53 mutations, with KDM5C emerging as a candidate tumour suppressor.

Whole-exome sequencing of 19 lesions and matched normal tissues from 13 cases of gastric-type SMMN-FGT found a markedly higher prevalence of pathogenic germline variants in cancer-predisposition genes than in common gynaecologic cancers (38.5% versus 4.4-8.6%). Two cases carried pathogenic BRCA1 variants, raising the possibility that SMMN-FGT belongs to a broader BRCA1-associated phenotypic spectrum. Somatic profiling identified TP53 mutations in 5 of 19 lesions (26.3%), 4 of which (80%) were malignant; gastric-type cervical adenocarcinoma, the commonest malignant subtype, harboured TP53 mutations in 3 of 7 lesions (42.9%) and no PIK3CA mutations, in contrast with conventional cervical cancers (27-41% PIK3CA). Clonal analysis nominated KDM5C as a candidate driver: overexpression reduced viability, migration and invasion and increased apoptosis, while knockdown had the opposite effect.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The practical message for the clinic is that an SMMN-FGT lesion, long attributed to STK11 alone, warrants broad germline investigation — a matter of interpreting exome or genome data already generated rather than of adding genes to a targeted panel. The series remains very small (13 cases), and two BRCA1 carriers are far too few to claim an extension of the BRCA1 spectrum: for now this is a lead, not a change in carrier surveillance. The KDM5C work, supported by in vitro function, belongs to tumour biology and carries no immediate germline implication.

Analysis by Dr Thibaut Benquey