title: Epigenome-wide ovarian cancer analysis identifies a methylation profile differentiating clear-cell histology with epigenetic silencing of the HERG K+ channel.
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.
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mine S
authors.initials: MS
authors.lastname: Cicek
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Larson
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Stacey J
authors.initials: SJ
authors.lastname: Winham
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Block
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.forename: Gottfried
authors.initials: G
authors.lastname: Konecny
authors.forename: Boris J
authors.initials: BJ
authors.lastname: Winterhoff
authors.forename: Habib
authors.initials: H
authors.lastname: Hamidi
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.forename: Janet E
authors.initials: JE
authors.lastname: Olson
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D000072237:ERG1 Potassium Channel; D044127:Epigenesis, Genetic; D057890:Epigenomics; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human