Clonal origins and divergent evolutionary relationships of synchronous multiple malignant neoplasms in gynecology...

Synchronous multiple malignant neoplasms (SMMNs) in gynecology involving the ovary, endometrium, and cervix are rare and pose a significant diagnostic challenge when the primary lesion is unclear.

We performed targeted genomic sequencing, immunohistochemical analysis and copy number analysis on multiple samples from one patient with simultaneous cancerous lesions in ovary, endometrium and cervix, to clarify tumor clonal origin and divergent evolutionary relationships.

Using blood-derived genomic DNA as reference, targeted sequencing of 1012 genes across endometrial, ovarian, and cervical sites identified two germline and 96 somatic mutations. A germline MSH2 splice acceptor site mutation confirmed Lynch syndrome. Tumor across distinct anatomical sites shared three genetic mutations: an MSH2 missense mutation, a FAT1 missense mutation, and an SH3GL1 in-frame deletion. These rare mutations of uncertain clinical significance support a shared clonal origin. Ovarian lesions showed the highest shared somatic mutation frequency, indicating an ovarian origin. Phylogenetic reconstruction revealed branched evolution, indicating metastasis from ovary to endometrium and cervix. Diverse mutation forms in ARID1A, PTEN, ERBB2, and PIK3CA across different lesions suggest convergent phenotypic evolution.

Next-generation sequencing precisely resolved the diagnostic dilemma of gynecologic SMMNs by delineating an ovarian origin and a complex evolutionary pattern, thereby proving critical for guiding personalized treatment and screening strategies, particularly in hereditary cancer syndromes.