Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation

Cancer. 2008 Apr 1;112(7):1489-502. doi: 10.1002/cncr.23323.


Background: Imprinted tumor suppressor genes may be particularly important in the pathogenesis of ovarian cancer. Two imprinted genes, paternally expressed 3 (PEG3) and aplasia Ras homologue member I (ARHI), are the most frequently down-regulated in ovarian cancers on gene expression arrays.

Methods: PEG3 and ARHI expression levels were evaluated with real-time reverse-transcriptase polymerase chain reaction (PCR) analysis. Promoter methylation was measured by pyrosequencing, and loss of heterozygosity (LOH) was detected by PCR-LOH assays.

Results: PEG3 was down-regulated in 75% and ARHI was down-regulated in 88% of 40 ovarian cancers. ARHI CpG islands I and II were hypermethylated in 13 of 42 ovarian cancers (31%) and in 5 of 42 ovarian cancers (12%), respectively, and hypermethylation was associated with reduced ARHI expression in all 18 samples of ovarian cancer with CpG island hypermethylation. PEG3 was hypermethylated in 11 of 42 ovarian cancers (26%), and PEG3 expression was down-regulated in 10 of those 11 cancers. LOH was detected in 8 of 35 informative cases for ARHI (23%) and in 5 of 25 informative cases for PEG3 (20%). PEG3 and ARHI expression was highly correlated in human ovarian cancers (correlation coefficient [R]=0.69; P< .0001). PEG3 and ARHI also were methylated concordantly in ovarian cancers (R=0.36; P= .019). Re-expression of PEG3, similar to that of ARHI, markedly inhibited ovarian cancer growth. ARHI and PEG3 expression could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A, consistent with the importance of promoter methylation and histone acetylation in regulating expression of both genes.

Conclusions: Loss of expression of the growth-inhibitory imprinted genes ARHI and PEG3 through promoter methylation, LOH, and other mechanisms may stimulate clonogenic growth and contribute to the pathogenesis of a majority of ovarian cancers.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / genetics
  • Adenocarcinoma, Clear Cell / secondary
  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / secondary
  • Carcinoma, Endometrioid / genetics
  • Carcinoma, Endometrioid / secondary
  • Case-Control Studies
  • CpG Islands
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / secondary
  • DNA Methylation*
  • DNA Primers / chemistry
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology
  • Genomic Imprinting*
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Loss of Heterozygosity
  • Oligonucleotide Array Sequence Analysis
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Ovary / metabolism
  • Ovary / pathology
  • Promoter Regions, Genetic / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • rho GTP-Binding Proteins / genetics*


  • DIRAS3 protein, human
  • DNA Primers
  • Kruppel-Like Transcription Factors
  • PEG3 protein, human
  • RNA, Messenger
  • rho GTP-Binding Proteins