Journal of the National Cancer Institute Advance Access originally published online on August 8, 2007
JNCI Journal of the National Cancer Institute 2007 99(16):1270-1273; doi:10.1093/jnci/djm069
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© The Author 2007. Published by Oxford University Press.
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Epigenetic Specificity of Loss of Imprinting of the IGF2 Gene in Wilms Tumors
Affiliations of authors: Center for Epigenetics, Institute of Basic Biomedical Sciences (HTB, LJB, MAR, APF) and Department of Medicine (HTB, LJB, MAR, APF), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, MD (MDF); Illumina, Inc, San Diego, CA (MB, EW, JBF)
Correspondence to: Andrew P. Feinberg, MD, MPH, Center for Epigenetics, Institute of Basic Biomedical Sciences and Department of Medicine, Johns Hopkins University School of Medicine, 1064 Ross, 720 Rutland Ave, Baltimore, MD 21205 (e-mail: afeinberg{at}jhu.edu).
Loss of imprinting (LOI) of the IGF2 gene (which encodes insulin-like growth factor II) is the most common genetic or epigenetic alteration in Wilms tumor; LOI involves aberrant activation of the normally repressed maternally inherited allele. We found previously that LOI of IGF2 occurs in approximately half of all Wilms tumors (i.e., those arising from lineage-committed nephrogenic progenitor cells). We investigated whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. We stratified 59 Wilms tumor samples by IGF2 LOI status by use of hot-stop reverse transcription–polymerase chain reaction and/or methylation analysis of the differentially methylated region of the H19 gene and identified 31 samples with and 28 without LOI. We used quantitative allele-specific expression analysis to determine whether six other imprinted genes (i.e., H19, KCNQ1, LIT1, TSSC5, GRB10, and MEG3) had subtle LOI. No statistically significant difference in allele-specific expression between Wilms tumor with or without LOI was found for LIT1, TSSC5, GRB10, and MEG3. For the KCNQ1 gene there was a slight difference between the groups with (37.0%, 95% confidence interval [CI] = 31.8% to 42.2%) and without (27.7%, 95% CI = 21.8% to 33.5%) LOI (P = .02 for F test of group differences in a mixed-effects model). For H19, we also found a slight difference between the groups with (7.5%, 95% CI = 2.4% to 12.7%) and without (2.2%, 95% CI = –3.2% to 7.6%) LOI of IGF2 (P = .15 for F test). In 27 tumor samples, we also used a microarray technique to analyze methylation of 378 genes, 38 of which were suspected or confirmed imprinted genes. We found that statistically significant alterations in only the differentially methylated region of the H19 gene were associated with LOI of IGF2. Thus, epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2.
| CONTEXT AND CAVEATS Prior knowledge Loss of imprinting (LOI) of the IGF2 gene is the most common genetic or epigenetic alteration in Wilms tumor and involves aberrant activation of the normally repressed maternally inherited allele. LOI of IGF2 occurs in approximately half of all Wilms tumors. Study design Molecular biologic study of 59 Wilms tumor samples to determine whether LOI of IGF2 is associated with relaxation of imprinting at loci other than IGF2 or with widespread alterations in DNA methylation. Contribution LOI of IGF2 in Wilms tumors appears epigenetically specific and is not associated with a generalized disruption of imprinting. Implications Epigenetic alterations in Wilms tumors are not widespread, supporting the gene and lineage specificity of LOI of IGF2. Thus, IGF2 might be a good pharmacologic target for drug development, without the usual substantial concerns about other preexisting genetic or epigenetic changes that would be selected for by the treatment. Limitations Only 59 tumors were examined. Not all imprinted genes or all potentially methylated sites could be examined.
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Manuscript received November 21, 2006; revised June 12, 2007; accepted June 15, 2007.
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J Natl Cancer Inst 2007 99: 1213.
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