title: Altered expression of imprinted genes in Wilms tumors.
abstract: Overexpression of insulin-like growth factor 2 (IGF2), an imprinted gene located on chromosome 11p15, has been reported as a characteristic feature in various embryonal tumors, including Wilms tumor (WT). Recent studies specified loss of imprinting (LOI) in a differential methylated region (DMR) of the IGF2/H19 cluster or loss of heterozygosity (LOH), respectively, uniparental disomy (UPD) being responsible for this overexpression. However, the role of other imprinted genes in the genesis of WT is still unknown. In the current study, we analyzed transcriptional activity of the imprinted genes IGF2, H19, NNAT, DLK1, RTL1, MEG3, and MEST as well as the methylation status of the DMR of the IGF2/H19 cluster in a panel of 32 WTs. Except for H19, we detected massive overexpression of all genes in the majority of WTs compared to normal renal tissue, which was most prominent for the paternally expressed genes IGF2, NNAT, and MEST. Alterations of the H19DMR were found in two-thirds of the WTs. Moreover, we have seen a strong correlation between the transcriptional activity of IGF2, NNAT and MEST and LOI/LOH of H19DMR, which was inverse for H19. Expression of DLK1, RTL1 and MEG3 does not correlate with LOI/LOH of H19DMR. Altogether, our findings suggest that over-expression of imprinted genes is common in WTs and correlates at least for some imprinted genes with LOI of H19DMR. Thus, it may be speculated that alterations of the DNA modification machinery drive erroneous setting of methylation marks in imprinting regions throughout the genome, which leads to the concomitant activation of imprinted genes in blastomagenesis.
authors.affiliation: Department of Pediatric Surgery, Research Laboratories, Ludwig-Maximilians-University of Munich, Lindwurmstrasse 2a, D-80337 Munich, Germany. jochen.hubertus@med.uni-muenchen.de
authors.forename: Jochen
authors.initials: J
authors.lastname: Hubertus
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.forename: Marietta
authors.initials: M
authors.lastname: Rottenkolber
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.forename: Maximilian
authors.initials: M
authors.lastname: Stehr
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Schweinitz
authors.forename: Roland
authors.initials: R
authors.lastname: Kappler
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting / Q000502:physiology*; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology
chemical_list: C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated