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- Title
Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel.
- Authors
Cicek, Mine S.; Koestler, Devin C.; Fridley, Brooke L.; Kalli, Kimberly R.; Armasu, Sebastian M.; Larson, Melissa C.; Wang, Chen; Winham, Stacey J.; Vierkant, Robert A.; Rider, David N.; Block, Matthew S.; Klotzle, Brandy; Konecny, Gottfried; Winterhoff, Boris J.; Hamidi, Habib; Shridhar, Viji; Fan, Jian-Bing; Visscher, Daniel W.; Olson, Janet E.; Hartmann, Lynn C.
- 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 × 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.
- Publication
Human Molecular Genetics, 2013, Vol 22, Issue 15, p3038
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddt160