title: Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer.
abstract: Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner.
authors.affiliation: Division of Gynecologic Oncology, Duke University Medical Center, Box 91012, Durham, NC 27708, USA. murph035@mc.duke.edu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Wen
authors.forename: Monique A
authors.initials: MA
authors.lastname: Spillman
authors.forename: Regina S
authors.initials: RS
authors.lastname: Whitaker
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Simel
authors.forename: Teresa D
authors.initials: TD
authors.lastname: Nichols
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
mesh_terms: D000483:Alleles; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D002277:Carcinoma / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017434:Protein Structure, Tertiary; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II