Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel

Mine S. Cicek, Devin C. Koestler, Brooke L. Fridley, Kimberly R. Kalli, Sebastian M. Armasu, Melissa C. Larson, Chen Wang, Stacey J. Winham, Robert A. Vierkant, David N. Rider, Matthew S. Block, Brandy Klotzle, Gottfried Konecny, Boris J. Winterhoff, Habib Hamidi, Viji Shridhar, Jian Bing Fan, Daniel W. Visscher, Janet E. Olson, Lynn C. HartmannMarina Bibikova, Jeremy Chien, Julie M. Cunningham, Ellen L. Goode

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Ovarian cancer remains the leading cause of death in women with gynecologic malignancies, despite surgical advances and the development of more effective chemotherapeutics. As increasing evidence indicates that clear-cell ovarian cancer may have unique pathogenesis, further understanding of molecular features may enable us to begin to understand the underlying biology and histology-specific information for improved outcomes. To study epigenetics in clear-cell ovarian cancer, fresh frozen tumor DNA (n = 485) was assayed on Illumina Infinium HumanMethylation450 BeadChips. We identified a clear-cell ovarian cancer tumor methylation profile (n = 163) which we validated in two independent replication sets (set 1, n = 163; set 2, n = 159), highlighting 22 CpG loci associated with nine genes (VWA1, FOXP1, FGFRL1, LINC00340, KCNH2, ANK1, ATXN2, NDRG21 and SLC16A11). Nearly all of the differentially methylated CpGs showed a propensity toward hypermethylation among clear-cell cases. Several loci methylation inversely correlated with tumor gene expression, most notably KCNH2 (HERG, a potassium channel) (P = 9.5 X 10-7), indicating epigenetic silencing. In addition, a predicted methylation class mainly represented by the clear-cell cases (20 clear cell out of 23 cases) had improved survival time. Although these analyses included only 30 clear-cell carcinomas, results suggest that loss of expression of KCNH2 (HERG) by methylation could be a good prognostic marker, given that overexpression of the potassium (K+) channel Eag family members promotes increased proliferation and results in poor prognosis. Validation in a bigger cohort of clear-cell tumors of the ovary is warranted.

Original languageEnglish (US)
Article numberddt160
JournalHuman molecular genetics
Volume22
Issue number15
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Cicek, M. S., Koestler, D. C., Fridley, B. L., Kalli, K. R., Armasu, S. M., Larson, M. C., Wang, C., Winham, S. J., Vierkant, R. A., Rider, D. N., Block, M. S., Klotzle, B., Konecny, G., Winterhoff, B. J., Hamidi, H., Shridhar, V., Fan, J. B., Visscher, D. W., Olson, J. E., ... Goode, E. L. (2013). Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel. Human molecular genetics, 22(15), [ddt160]. https://doi.org/10.1093/hmg/ddt160