title: Isocitrate dehydrogenase 1/2 mutational analyses and 2-hydroxyglutarate measurements in Wilms tumors.
abstract: BACKGROUND
  L-2-Hydroxyglutaric aciduria (L-2-HGA) is an uncommon inborn error of metabolism, in which the patients are predisposed to develop brain tumors. Elevated levels of D-2-hydroxyglutarate have been demonstrated with malignant gliomas and myeloid leukemias associated with somatic mutations of the genes encoding NADP(+)-dependent isocitrate dehydrogenases (IDH1 and IDH2, respectively). Recently, we noted a Wilms tumor in a child with L-2-HGA. Given the accumulating evidence that both enantiomers of 2-hydroxyglutarate are associated with cellular transformation, we investigated if sporadic Wilms tumors are associated with IDH1 or IDH2 mutations or with elevated levels of 2-hydroxyglutarate.
  
  
  METHODS
  We retrieved 21 frozen Wilms tumor tissues. In 20 cases, we sequenced exon 4 and flanking intronic regions of IDH1 and IDH2. In all 21 cases, we measured 2-hydroxyglutarate levels by liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  We did not find mutations at the hot spots IDH1 codon 132 or IDH2 codon 172. Two cases (1 with favorable histology and 1 with unfavorable histology) showed heterozygous change c.211G>A (p.Val71Ile) in IDH1, a change previously reported as a mutation but listed as a single nucleotide polymorphism in the NCBI SNP database. We did not find increased levels of 2-hydroxygluatric acid in any sample.
  
  
  CONCLUSIONS
  Our results suggest that IDH1 codon 132 or IDH2 codon 172 mutations or elevated 2-hydroxyglutarate levels do not play a role in the biology of sporadic Wilms tumors. The significance of heterozygous change c.211G>A (p.Val71Ile) in IDH1, seen in two tumors, is not clear.
authors.affiliation: Department of Pathology, Children's Medical Center and UT Southwestern Medical Center, Dallas, Texas 75390, USA. dinesh.rakheja@utsouthwestern.edu
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.forename: Midori
authors.initials: M
authors.lastname: Mitui
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boriack
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
mesh_terms: D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D005977:Glutarates; D012333:RNA, Messenger; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human