title: Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene.
abstract: Cancers arise through accumulating genetic and epigenetic alterations, considered relevant for phenotype and approaches to targeting new therapies. We investigated a unique collection of endometrial cancer precursor samples and clinically annotated primary and metastatic lesions for two evolutionary and functionally related transcription factors, CCCTC-binding factor (zinc finger protein) (CTCF) and its paralogue CTCF-like factor, also denoted Brother of the Regulator of Imprinted Sites (CTCFL/BORIS). CTCF, a chromatin modeling- and transcription factor, is normally expressed in a ubiquitous fashion, while CTCFL/BORIS is restricted to the testis. In cancer, CTCF is thought to be a tumor suppressor, while CTCFL/BORIS has been suggested as an oncogene. CTCF mutations were identified in 13%, with CTCF hotspot frameshift mutations at p.T204, all observed solely in the endometrioid subtype, but with no association with outcome. Interestingly, CTCFL/BORIS was amongst the top ranked genes differentially expressed between endometrioid and non-endometrioid tumors, and increasing mRNA level of CTCFL/BORIS was highly significantly associated with poor survival. As aberrant CTCFL/BORIS expression might relate to loss of methylation, we explored methylation status in clinical samples from complex atypical hyperplasia, through primary tumors to metastatic lesions, demonstrating a pattern of DNA methylation loss during disease development and progression in line with the increase in CTCFL/BORIS mRNA expression observed. Thus, CTCF and CTCFL/BORIS are found to diverge in the different subtypes of endometrial cancer, with CTCFL/BORIS activation through demethylation from precursors to metastatic lesions. We thus propose, CTCFL/BORIS as an Epi-driver gene in endometrial cancer, suggesting a potential for future vaccine development.
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Erling A
authors.initials: EA
authors.lastname: Hoivik
authors.forename: Kanthida
authors.initials: K
authors.lastname: Kusonmano
authors.forename: Mari K
authors.initials: MK
authors.lastname: Halle
authors.forename: Anna
authors.initials: A
authors.lastname: Berg
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wik
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.forename: Kjell
authors.initials: K
authors.lastname: Petersen
authors.forename: Anne M
authors.initials: AM
authors.lastname: Oyan
authors.forename: Karl-Henning
authors.initials: KH
authors.lastname: Kalland
authors.forename: Camilla
authors.initials: C
authors.lastname: Krakstad
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D000368:Aged; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors