RT Journal Article
SR Electronic
T1 Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 330597
DO 10.1101/330597
A1 Kate Lawrenson
A1 Marcos A.S. Fonseca
A1 Felipe Segato
A1 Janet M. Lee
A1 Rosario I. Corona
A1 Ji-Heui Seo
A1 Simon Coetzee
A1 Yvonne G. Lin
A1 Tanja Pejovic
A1 Paulette Mhawech-Fauceglia
A1 Ronny Drapkin
A1 Beth Y. Karlan
A1 Dennis J. Hazelett
A1 Matthew L. Freedman
A1 Simon A. Gayther
A1 Houtan Noushmehr
YR 2018
UL http://biorxiv.org/content/early/2018/05/25/330597.abstract
AB Historically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj = 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P < 2.2 × 10−16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.