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Cell Rep. 2019 Dec 10;29(11):3726-3735.e4. doi: 10.1016/j.celrep.2019.10.122.

A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development.

Author information

1
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: kate.lawrenson@cshs.org.
2
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
3
Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
4
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
5
Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA.
6
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
8
Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, University of Southern California/Keck School of Medicine, Los Angeles, Los Angeles, CA, USA.
9
Division of Gynecologic Oncology, Department of Obstetrics-Gynecology, University of Southern California/Keck School of Medicine, Los Angeles, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
10
Aurora Diagnostics, Austin, TX, USA.
11
Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA.
12
Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Electronic address: simon.gayther@cshs.org.
13
Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, USA; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil. Electronic address: hnoushm1@hfhs.org.

Abstract

Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10-4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10-4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10-16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs.

KEYWORDS:

RNA-seq; SOX18; dual origins; fallopian tube secretory epithelial cell; high-grade serous ovarian cancer; machine learning; one-class logistic regression models; ovarian surface epithelial cell; single-cell RNA-seq; super enhancers; transcription factors

PMID:
31825847
DOI:
10.1016/j.celrep.2019.10.122
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