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. PROCEDURE: 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.
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. PROCEDURE: 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: Andrew R Mullen; Zeping Hu; Xiaolei Shi; Lei Jiang; Lindsey K Boroughs; Zoltan Kovacs; Richard Boriack; Dinesh Rakheja; Lucas B Sullivan; W Marston Linehan; Navdeep S Chandel; Ralph J DeBerardinis Journal: Cell Rep Date: 2014-05-22 Impact factor: 9.423
Authors: Changho Choi; Sandeep K Ganji; Ralph J DeBerardinis; Kimmo J Hatanpaa; Dinesh Rakheja; Zoltan Kovacs; Xiao-Li Yang; Tomoyuki Mashimo; Jack M Raisanen; Isaac Marin-Valencia; Juan M Pascual; Christopher J Madden; Bruce E Mickey; Craig R Malloy; Robert M Bachoo; Elizabeth A Maher Journal: Nat Med Date: 2012-01-26 Impact factor: 53.440
Authors: Martijn Kranendijk; Eduard A Struys; Gajja S Salomons; Marjo S Van der Knaap; Cornelis Jakobs Journal: J Inherit Metab Dis Date: 2012-03-06 Impact factor: 4.982
Authors: P S Ward; J R Cross; C Lu; O Weigert; O Abel-Wahab; R L Levine; D M Weinstock; K A Sharp; C B Thompson Journal: Oncogene Date: 2011-09-26 Impact factor: 8.756
Authors: An-Ping Lin; Saman Abbas; Sang-Woo Kim; Manoela Ortega; Hakim Bouamar; Yissela Escobedo; Prakash Varadarajan; Yuejuan Qin; Jessica Sudderth; Eduard Schulz; Alexander Deutsch; Sumitra Mohan; Peter Ulz; Peter Neumeister; Dinesh Rakheja; Xiaoli Gao; Andrew Hinck; Susan T Weintraub; Ralph J DeBerardinis; Heinz Sill; Patricia L M Dahia; Ricardo C T Aguiar Journal: Nat Commun Date: 2015-07-16 Impact factor: 17.694