Oncotarget

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, Helga B. Salvesen

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

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Abstract

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.

Correspondence:

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

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.

Author Information

Erling A. Hoivik
Primary Contact  _

1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

Kanthida Kusonmano
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 3Computational Biology Unit, University of Bergen, Norway.

Mari K. Halle
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

Anna Berg
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

Elisabeth Wik
4Centre for Cancer Biomarkers, Department of Clinical Medicine, University of Bergen, Bergen, Norway. Department of Clinical Science, University of Bergen, Bergen, Norway. 5Department of Pathology, Haukeland University Hospital, Bergen, Norway.

Henrica M. J. Werner
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway.

Kjell Petersen
3Computational Biology Unit, University of Bergen, Norway.

Anne M. Oyan
2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway. 6Department of Microbiology, Haukeland University Hospital, Bergen, Norway.

Karl-Henning Kalland
2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway. 6Department of Microbiology, Haukeland University Hospital, Bergen, Norway.

Camilla Krakstad
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

Jone Trovik
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.

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

Helga B. Salvesen
1Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway. 2Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.


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