Research Papers:

Hypomethylation of the CTCFL/BORIS promoter and aberrant expression during endometrial cancer progression suggests a role as an Epi-driver gene

Erling A. Hoivik _, Kanthida Kusonmano, Mari K. Halle, Anna Berg, Elisabeth Wik, Henrica M. J. Werner, Kjell Petersen, Anne M. Oyan, Karl-Henning Kalland, Camilla Krakstad, Jone Trovik, Martin Widschwendter and Helga B. Salvesen

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Oncotarget. 2014; 5:1052-1061. https://doi.org/10.18632/oncotarget.1697

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Erling A. Hoivik1,2, Kanthida Kusonmano1,3, Mari K. Halle1,2, Anna Berg1,2, Elisabeth Wik4,5, Henrica M. J. Werner1, Kjell Petersen3, Anne M. Oyan2,6, Karl-Henning Kalland2,6, Camilla Krakstad1,2, Jone Trovik1,2, Martin Widschwendter7, Helga B. Salvesen1,2

1 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

2 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

3 Computational Biology Unit, University of Bergen, Norway.

4 Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway. 

5 Department of Pathology, Haukeland University Hospital, Bergen, Norway.

6 Department of Microbiology, Haukeland University Hospital, Bergen, Norway.

7 Department of Women’s Cancer, University College London Elizabeth Garrett Anderson Institute for Women’s Health, University College London, United Kingdom.


Erling A. Hoivik, email:

Keywords: CTCFL/BORIS, CTCF, metastasis, recurrence, epi-driver gene

Received: December 13, 2013 Accepted: January 26, 2014 Published: January 28, 2014


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.

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