Pathogenesis of ovarian cancer

Epithelial ovarian cancer (EOC) is a heterogeneous disease with five histotypes: serous (high-grade and low-grade), endometrioid, clear cell and mucinous carcinoma. New evidences suggest that the majority of EOC are of extra-ovarian origin. We used next-generation sequencing to investigate the cell of origin of high-grade serous ovarian carcinoma (HGSOC) and mucinous ovarian carcinoma (MOC). We analyzed exome-wide sequence and structural analyses of multiple tumor samples from five individuals with advanced stage sporadic HGSOC. Our results suggest that ovarian cancer is a disease of the fallopian tubes, with the development of p53 signatures and serous tubal intraepithelial carcinoma as early events. The subsequent formation of a cancer in the ovaries represents a seeding event from a primary tumor in the fallopian tube that already contains sequence and structural alterations in key driver genes, including TP53, PI3K pathway, and BRCA1/BRCA2 genes. Our work could have implication for screening and early diagnosis of HGSOC. In a separate work, we used unsupervised clustering of gene-expression profile of different histotype of ovarian tumors, their eutopic tissues (ovarian surface epithelium and fallopian tube) and single-cell RNA-sequencing of primordial germ cells (PGCs). We observed that mucinous ovarian tumors (borderline and carcinoma) cluster more closely to PGCs than their eutopic tissue of origin. Our work brings a new and plausible explanation of the clinical and epidemiologic characteristics of MOC and could help into developing new target therapies for this rare and chemoresistant tumor