Hai Yan

Publications (52)598.82 Total impact

• Article: Clinic-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations.

  Giselle Y Lopez, Gerald A Grant, Herbert E Fuchs, Linda G Leithe, Sridharan Gururangan, Darell D Bigner, Hai Yan, Roger E McLendon, Yiping He
  Neuropathology and Applied Neurobiology 05/2013; · 3.80 Impact Factor
• Article: Isocitrate dehydrogenase 1: what it means to the neurosurgeon.

  Tiffany R Hodges, Bryan D Choi, Darell D Bigner, Hai Yan, John H Sampson
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  ABSTRACT: Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.
  Journal of Neurosurgery 04/2013; · 2.96 Impact Factor
• Article: Exomic Sequencing of Four Rare Central Nervous System Tumor Types.

  Chetan Bettegowda, Nishant Agrawal, Yuchen Jiao, Yuxuan Wang, Laura D Wood, Fausto J Rodriguez, Ralph H Hruban, Gary L Gallia, Zev A Binder, Callen J Riggins, [......], Stephen Keir, Sueli Shinjo, Suely Marie, Roger McLendon, George Jallo, Bert Vogelstein, Darell Bigner, Hai Yan, Kenneth W Kinzler, Nickolas Papadopoulos
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  ABSTRACT: A heterogeneous population of uncommon neoplasms of the central nervous system (CNS) cause significant morbidity and mortality. To explore their genetic origins, we sequenced the exomes of 12 pleomorphic xanthoastrocytomas (PXA), 17 non-brainstem pediatric glioblastomas (PGBM), 8 intracranial ependymomas (IEP) and 8 spinal cord ependymomas (SCEP). Analysis of the mutational spectra revealed that the predominant single base pair substitution was a C:G>T:A transition in each of the four tumor types. Our data confirm the critical roles of several known driver genes within CNS neoplasms, including TP53 and ATRX in PGBM, and NF2 in SCEPs. Additionally, we show that activating BRAF mutations play a central role in both low and high grade glial tumors. Furthermore, alterations in genes coding for members of the mammalian target of rapamycin (mTOR) pathway were observed in 33% of PXA. Our study supports the hypothesis that pathologically similar tumors arising in different age groups and from different compartments may represent distinct disease processes with varied genetic composition.
  Oncotarget 04/2013; · 4.78 Impact Factor
• Article: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

  Patrick J Killela, Zachary J Reitman, Yuchen Jiao, Chetan Bettegowda, Nishant Agrawal, Luis A Diaz, Allan H Friedman, Henry Friedman, Gary L Gallia, Beppino C Giovanella, [......], Tian-Li Wang, Nicolas Wentzensen, Laura D Wood, Ming Zhang, Roger E McLendon, Darell D Bigner, Kenneth W Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Hai Yan
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  ABSTRACT: Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
  Proceedings of the National Academy of Sciences 03/2013; · 9.68 Impact Factor
• Article: Disruption of wild type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.

  Genglin Jin, Zachary J Reitman, Chritopher G Duncan, Ivan Spasojevic, David M Gooden, B Ahmed Rasheed, Rui Yang, Giselle Y Lopez, Yiping He, Roger E McLendon, Darell D Bigner, Hai Yan
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  ABSTRACT: Point mutations at Arg132 of the cytoplasmic NADP+-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain-of-function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild type IDH1 allele (heterozygous) in cancer. Here, we identify two gliomas which underwent loss of the wild type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild type IDH1 compared with glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild type IDH1 to cancer cell D-2HG production, we established an IDH1-Mutated Astrocytoma cell line (IMA) from a WHO grade III anaplastic astrocytoma. Disruption of the wild type IDH1 allele in IMA cells by gene-targeting resulted in an 87-fold decrease in cellular D-2HG levels, demonstrating that both wild type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.
  Cancer Research 11/2012; · 7.86 Impact Factor
• Article: Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

  Changcun Guo, Chun-Chi Chang, Matthew Wortham, Lee H Chen, Dawn N Kernagis, Xiaoxia Qin, Young-Wook Cho, Jen-Tsan Chi, Gerald A Grant, Roger E McLendon, Hai Yan, Kai Ge, Nickolas Papadopoulos, Darell D Bigner, Yiping He
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  ABSTRACT: Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.
  Proceedings of the National Academy of Sciences 10/2012; 109(43):17603-8. · 9.68 Impact Factor
• Article: A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation.

  Christopher G Duncan, Benjamin G Barwick, Genglin Jin, Carlo Rago, Priya Kapoor-Vazirani, Doris R Powell, Jen Tsan Chi, Darell D Bigner, Paula M Vertino, Hai Yan
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  ABSTRACT: Monoallelic point mutations of the NADP(+)-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1(R132H) allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1(R132H/WT) mutation induces widespread alterations in DNA methylation, including hypermethylation of 2,010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors, as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1(R132H/WT)-mediated DNA methylation change is largely dependent upon pre-existing DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes downregulated in IDH1(R132H/WT) knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1(R132H/WT) mutants in driving epigenetic instability in human cancer cells.
  Genome Research 08/2012; · 13.61 Impact Factor
• Article: Mutant IDH1 is required for IDH1 mutated tumor cell growth.

  Genglin Jin, Christopher J Pirozzi, Lee H Chen, Giselle Y Lopez, Christopher G Duncan, Jie Feng, Ivan Spasojevic, Darell D Bigner, Yiping He, Hai Yan
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  ABSTRACT: Frequent somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in gliomas, acute myeloid leukemias, chondrosarcomas, and other cancers, providing a likely avenue for targeted cancer therapy. However, whether mutant IDH1 protein is required for maintaining IDH1 mutated tumor cell growth remains unknown. Here, using a genetically engineered inducible system, we report that selective suppression of endogenous mutant IDH1 expression in HT1080, a fibrosarcoma cell line with a native IDH1R132C heterozygous mutation, significantly inhibits cell proliferation and decreases clonogenic potential. Our findings offer insights into changes that may contribute to the inhibition of cell proliferation and offer a strong preclinical rationale for utilizing mutant IDH1 as a valid therapeutic target.
  Oncotarget 08/2012; 3(8):774-82. · 4.78 Impact Factor
• Article: Frequent ATRX, CIC, and FUBP1 mutations refine the classification of malignant gliomas.

  Yuchen Jiao, Patrick J Killela, Zachary J Reitman, Ahmed B Rasheed, Christopher M Heaphy, Roeland F de Wilde, Fausto J Rodriguez, Sergio Rosemberg, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, [......], Matthias Holdhoff, Peter Burger, Roger McLendon, Darell D Bigner, Bert Vogelstein, Alan K Meeker, Kenneth W Kinzler, Nickolas Papadopoulos, Luis A Diaz, Hai Yan
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  ABSTRACT: Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.
  Oncotarget 08/2012; 3(7):709-22. · 4.78 Impact Factor
• Article: Apples to origins: identifying brain tumor stem cell genes by comparing transcriptomes of normal and cancer stem cells.

  Matthew Wortham, Hai Yan
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  ABSTRACT: The mechanisms whereby medulloblastoma stem cells coordinate tumor propagation are poorly understood. Using microarray analysis, Corno and colleagues draw parallels and distinctions between medulloblastoma stem cells from the Ptch(+/-) mouse and normal neural stem cells, identifying Ebf3 as a cancer stem cell-specific transcript critical for tumor growth.
  Cancer discovery. 06/2012; 2(6):492-4.
• Article: Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor.

  Meihua Li, Will Lockwood, Maria Zielenska, Paul Northcott, Young Shing Ra, Eric Bouffet, Maisa Yoshimoto, James T Rutka, Hai Yan, Michael D Taylor, Charles Eberhart, Cynthia E Hawkins, Wan Lam, Jeremy A Squire, Annie Huang
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  ABSTRACT: Embryonal brain tumors, which include medulloblastoma and the more aggressive supratentorial primitive neuroectodermal tumor (sPNET), comprise one of the largest group of malignant pediatric brain tumors. We observed in high resolution array comparative genomic hybridization and polymerase chain reaction analyses that several different components of the CDK/CYCLIND/pRB regulatory complex, including the CDK4/6 and CCND1/2 loci, are targets of gene amplification in medulloblastoma and sPNET. CDK6 and CCND1 gene amplification were respectively most common and robust, and overall CDK/CYCLIND gene amplification was more commonly observed in sPNET (25%) than medulloblastoma (1-5%). CDK6 overexpression enhanced in vitro and in vivo oncogenicity and endogenous CDK6 or CCND1 knockdown decreased pRB phosphorylation and impaired cell cycle progression in both medulloblastoma and sPNET cell lines. Although animal models implicate the pRB tumor suppressor pathway in medulloblastoma and sPNET, mutations of RB1 or the related INK4 tumor suppressor loci are rare in primary human tumors. Our data suggest that CDK/CYCLIND gene amplification may represent important mechanisms for functional inactivation of pRB in medulloblastoma and sPNET.
  Cancer Genetics 05/2012; 205(5):220-31.
• Source

  Available from: PubMed Central

  Article: Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells.

  Matthew Wortham, Genglin Jin, Julia Lailai Sun, Darell D Bigner, Yiping He, Hai Yan
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  ABSTRACT: Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation.
  PLoS ONE 01/2012; 7(4):e36211. · 4.09 Impact Factor
• Article: Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types.

  Siân Jones, Meng Li, D Williams Parsons, Xiaosong Zhang, Jelle Wesseling, Petra Kristel, Marjanka K Schmidt, Sanford Markowitz, Hai Yan, Darell Bigner, [......], James R Eshleman, Christine A Iacobuzio-Donahue, Michael Goggins, Anirban Maitra, Sami N Malek, Steve Powell, Bert Vogelstein, Kenneth W Kinzler, Victor E Velculescu, Nickolas Papadopoulos
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  ABSTRACT: Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.
  Human Mutation 01/2012; 33(1):100-3. · 5.69 Impact Factor
• Article: Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target.

  Changcun Guo, Christopher J Pirozzi, Giselle Y Lopez, Hai Yan
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  ABSTRACT: Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
  Current opinion in neurology 12/2011; 24(6):648-52. · 5.43 Impact Factor
• Article: Mutations in CIC and FUBP1 contribute to human oligodendroglioma.

  Chetan Bettegowda, Nishant Agrawal, Yuchen Jiao, Mark Sausen, Laura D Wood, Ralph H Hruban, Fausto J Rodriguez, Daniel P Cahill, Roger McLendon, Gregory Riggins, Victor E Velculescu, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, Bert Vogelstein, Darell Bigner, Hai Yan, Nickolas Papadopoulos, Kenneth W Kinzler
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  ABSTRACT: Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.
  Science 08/2011; 333(6048):1453-5. · 31.20 Impact Factor
• Article: Altered telomeres in tumors with ATRX and DAXX mutations.

  Christopher M Heaphy, Roeland F de Wilde, Yuchen Jiao, Alison P Klein, Barish H Edil, Chanjuan Shi, Chetan Bettegowda, Fausto J Rodriguez, Charles G Eberhart, Sachidanand Hebbar, [......], Darell D Bigner, Sueli Mieko Oba-Shinjo, Suely Kazue Nagahashi Marie, Gregory J Riggins, Kenneth W Kinzler, Bert Vogelstein, Ralph H Hruban, Anirban Maitra, Nickolas Papadopoulos, Alan K Meeker
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  ABSTRACT: The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.
  Science 06/2011; 333(6041):425. · 31.20 Impact Factor
• Article: Genomic alterations and the pathogenesis of glioblastoma.

  Christopher G Duncan, Hai Yan
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  ABSTRACT: Comment on: Duncan CG, et al. Oncotarget 2010; 1:265-77.
  Cell cycle (Georgetown, Tex.) 04/2011; 10(8):1174-5. · 5.36 Impact Factor
• Article: Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

  Zachary J Reitman, Genglin Jin, Edward D Karoly, Ivan Spasojevic, Jian Yang, Kenneth W Kinzler, Yiping He, Darell D Bigner, Bert Vogelstein, Hai Yan
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  ABSTRACT: Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.
  Proceedings of the National Academy of Sciences 02/2011; 108(8):3270-5. · 9.68 Impact Factor
• Source

  Available from: PubMed Central

  Article: 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.

  Genglin Jin, Zachary J Reitman, Ivan Spasojevic, Ines Batinic-Haberle, Jian Yang, Oleg Schmidt-Kittler, Darell D Bigner, Hai Yan
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  ABSTRACT: Gliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both. We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein). Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis.
  PLoS ONE 01/2011; 6(2):e16812. · 4.09 Impact Factor
• Article: The genetic landscape of the childhood cancer medulloblastoma.

  D Williams Parsons, Meng Li, Xiaosong Zhang, Siân Jones, Rebecca J Leary, Jimmy Cheng-Ho Lin, Simina M Boca, Hannah Carter, Josue Samayoa, Chetan Bettegowda, [......], Peter C Burger, Gregory J Riggins, Rachel Karchin, Giovanni Parmigiani, Darell D Bigner, Hai Yan, Nick Papadopoulos, Bert Vogelstein, Kenneth W Kinzler, Victor E Velculescu
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  ABSTRACT: Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
  Science 01/2011; 331(6016):435-9. · 31.20 Impact Factor