title: Gene expression analyses support fallopian tube epithelium as the cell of origin of epithelial ovarian cancer.
abstract: Folate receptor alpha (FOLR1/FRA) is reported to be overexpressed in epithelial ovarian cancers (EOC), especially the serous histotype. Further, while dysregulation of the folate-dependent 1-carbon cycle has been implicated in tumorogenesis, little is known relative to the potential mechanism of action of FOLR1 expression in these processes. We therefore investigated the expression of FOLR1, other folate receptors, and genes within the 1-carbon cycle in samples of EOC, normal ovary and fallopian tube on a custom TaqMan Low Density Array. Also included on this array were known markers of EOC such as MSLN, MUC16 and HE4. While few differences were observed in the expression profiles of genes in the 1-carbon cycle, genes previously considered to be overexpressed in EOC (e.g., FOLR1, MSLN, MUC16 and HE4) showed significantly increased expression when comparing EOC to normal ovary. However, when the comparator was changed to normal fallopian tube, these differences were abolished, supporting the hypothesis that EOC derives from fallopian fimbriae and, further, that markers previously considered to be upregulated or overexpressed in EOC are most likely not of ovarian origin, but fallopian in derivation. Our findings therefore support the hypothesis that the cell of origin of EOC is tubal epithelium.
authors.affiliation: Department of Translational Medicine and Diagnostics, Morphotek, Inc., 210 Welsh Pool Rd., Exton, PA 19341, USA. doshannessy@morphotek.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Shannessy
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Jackson
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Twine
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Hoffman
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dezso
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Agoulnik
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Somers
mesh_terms: D000328:Adult; D000368:Aged; D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism; D002244:Carbon / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D016000:Cluster Analysis; D005185:Fallopian Tube Neoplasms / Q000378:metabolism / Q000473:pathology; D005187:Fallopian Tubes / Q000378:metabolism*; D005260:Female; D058975:Folate Receptor 1 / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D000090204:Mesothelin; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D025341:Principal Component Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D018394:CA-125 Antigen; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; C451759:MUC16 protein, human; D008565:Membrane Proteins; D011506:Proteins; D011987:Receptors, Steroid; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D002244:Carbon; D000090204:Mesothelin