Mucinous ovarian tumors (MOT) are among the rarest and least studied epithelial ovarian neoplasms. Teratoma-associated MOT have been shown to be of germ cell origin. However, the pathogenesis of MOT not associated with teratoma remains unclear. Recent exome sequencing studies revealed similarities between MOT and mucinous cystic neoplasms (MCN) of the pancreas with frequent mutations in KRAS and RNF43.
Here we investigated the clinical characteristics of a series of 23 MCN and 287 MOT, which included age at diagnosis, sex, stage and exposure to smoking. We compared the immunohistochemical patterns of 23 MCN and 18 MOT (CK7, CK20, CDX2, MUC2, PAX8, SMAD4 and ß-catenin). We analyzed the gene expression profile (GEP) of 19 normal pancreatic tissues, 36 pancreatic ductal adenocarcinomas (PDAC), 6 MCN, 8 MOT, 27 normal fallopian tubes (FT), 13 high-grade serous ovarian carcinomas (HGSOC), 6 ovarian surface epithelium (OSE), 2 human PGCs and single cell RNA-sequencing of 5 primordial germ cells (PGC).
We observed that both MOT and MCN occur mainly in young women that have been exposed to smoking and they are frequently diagnosed at early stages. Both tumors have similar immunohistochemical phenotype, mainly CK7 + CK20-MUC2-CDX2-. Thus, we hypothesize that MCN and MOT would share a common cell of origin, primordial germ cells (PGCs) that stopped in the dorsal pancreas during their descent to gonads during early human embryogenesis. We compared GEP of MOT, HGSOC, OSE, FT and PGCs. Alterations in MOT correlated more with PGCs whereas HGSOC correlated with OSE or FT. We also compared GEP of normal pancreatic tissue, PDAC, pancreatic MCN and PGCs. Molecular alterations in pancreatic MCN correlated more with PGCs whereas PDAC relied on normal pancreatic tissue.
These finding support a common molecular pathway for the development of MCN and MOT and suggest that both tumors can derive from PGCs. Pancreatic MCN would arise from embryological remnants of PGCs that stop in the pancreas during early developement. In the ovaries, MOT can develop from PGCs that would not undergo oogonia.
Clinical trial identification
Legal entity responsible for the study
Fondation de France, Arthur Sachs/Harvard
All authors have declared no conflicts of interest.