Hai Yan, MD, PhD

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Professor of Pathology
Professor of Pharmacology and Cancer Biology
Department / Division:
Pathology / Pathology Research
Address:
199B Msrb
Research Drive
Durham, NC 27710
Office Telephone:
(919) 668-7850
Training:
  • MD, Beijing Medical University (China), 1991
  • PhD, Columbia University, 1997
Research Interests:
Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of driver mutations involved in the genesis and progression of brain cancers.  Gliomas are the most common type of primary brain tumor. Through genomic studies, we have identified mutations in IDH1 and IDH2 in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a neomorphic activity. A new metabolite produced by the glioma cells impacts on chromatin modulation and genome methylation.  Malignant cells must maintain their telomeres. We identified several different tumor types exhibiting a high frequency of TERT promoter mutations, including several glioma subtypes. Conversely, we found a low frequency of TERT promoter mutations in many common epithelial tumors.  In gliomas, we found that TERT promoter mutations were mutually exclusive with ATRX alterations, which are associated with activation of the ALT pathway for telomere maintenance. These findings show that TERT promoter mutations are frequent driver events in many human cancers, particularly those that arise from tissues with low rates of self-renewal. Our long-term goal is to develop a novel molecular-based glioma classification system and a targeted therapy on the basis of IDH1 and TERT mutations. To provide novel avenues for development of anticancer therapeutics, studies involving cell line and animal models, enzymatic study, metabolome and epigenome, are being investigated to determine the consequences of IDH1 and TERT mutations on cancer cells.
Representative Publications:
  • Jin, G; Reitman, ZJ; Duncan, CG; Spasojevic, I; Gooden, DM; Rasheed, BA; Yang, R; Lopez, GY; He, Y; McLendon, RE; Bigner, DD; Yan, H. Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer Research. 2013;73:496-501.  Abstract
  • Duncan, CG; Barwick, BG; Jin, G; Rago, C; Kapoor-Vazirani, P; Powell, DR; Chi, JT; Bigner, DD; Vertino, PM; Yan, H. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Research. 2012;22:2339-2355.  Abstract
  • Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget. 2012;3:709-722.  Abstract
  • Jin, G; Pirozzi, CJ; Chen, LH; Lopez, GY; Duncan, CG; Feng, J; Spasojevic, I; Bigner, DD; He, Y; Yan, H. Mutant IDH1 is required for IDH1 mutated tumor cell growth. Oncotarget. 2012;3:774-782.  Abstract
  • Koivunen, P; Lee, S; Duncan, CG; Lopez, G; Lu, G; Ramkissoon, S; Losman, JA; Joensuu, P; Bergmann, U; Gross, S; Travins, J; Weiss, S; Looper, R; Ligon, KL; Verhaak, RG; Yan, H; Kaelin, WG. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483:484-488.  Abstract
  • Reitman, ZJ; Choi, BD; Spasojevic, I; Bigner, DD; Sampson, JH; Yan, H. Enzyme redesign guided by cancer-derived IDH1 mutations. Nature Chemical Biology. 2012;8:887-889.  Abstract
  • Wortham, M; Jin, G; Sun, JL; Bigner, DD; He, Y; Yan, H. Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells. PLoS One. 2012;7:e36211.  Abstract
  • Bettegowda, C; Agrawal, N; Jiao, Y; Sausen, M; Wood, LD; Hruban, RH; Rodriguez, FJ; Cahill, DP; McLendon, R; Riggins, G; Velculescu, VE; Oba-Shinjo, SM; Marie, SK; Vogelstein, B; Bigner, D; Yan, H; Papadopoulos, N; Kinzler, KW. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333:1453-1455.  Abstract
  • Heaphy, CM; de Wilde, RF; Jiao, Y; Klein, AP; Edil, BH; Shi, C; Bettegowda, C; Rodriguez, FJ; Eberhart, CG; Hebbar, S; Offerhaus, GJ; McLendon, R; Rasheed, BA; He, Y; Yan, H; Bigner, DD; Oba-Shinjo, SM; Marie, SK; Riggins, GJ; Kinzler, KW; Vogelstein, B; Hruban, RH; Maitra, A; Papadopoulos, N; Meeker, AK. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333:425.  Abstract
  • Jin, G; Reitman, ZJ; Spasojevic, I; Batinic-Haberle, I; Yang, J; Schmidt-Kittler, O; Bigner, DD; Yan, H. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS One. 2011;6:e16812.  Abstract
  • Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SK; Shinjo, SM; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G; Bigner, DD; Yan, H; Papadopoulos, N; Vogelstein, B; Kinzler, KW; Velculescu, VE. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331:435-439.  Abstract
  • Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proceedings of the National Academy of Sciences of USA. 2011;108:3270-3275.  Abstract
  • Adamson, DC; Shi, Q; Wortham, M; Northcott, PA; Di, C; Duncan, CG; Li, J; McLendon, RE; Bigner, DD; Taylor, MD; Yan, H. OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Research. 2010;70:181-191.  Abstract
  • Reitman, ZJ; Yan, H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. Journal of National Cancer Institute. 2010;102:932-941.  Abstract
  • Duncan, CG; Leary, RJ; Lin, JC; Cummins, J; Di, C; Schaefer, CF; Wang, TL; Riggins, GJ; Edwards, J; Bigner, D; Kopelovich, L; Vogelstein, B; Kinzler, KW; Velculescu, VE; Yan, H. Identification of microbial DNA in human cancer. BMC Medical Genomics. 2009;2:22.  Abstract
  • Lu, Z; Zhou, L; Killela, P; Rasheed, AB; Di, C; Poe, WE; McLendon, RE; Bigner, DD; Nicchitta, C; Yan, H. Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress. Cancer Research. 2009;69:9105-9111.  Abstract
  • Yan, H; Bigner, DD; Velculescu, V; Parsons, DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Research. 2009;69:9157-9159.  Abstract
  • Yan, H; Parsons, DW; Jin, G; McLendon, R; Rasheed, BA; Yuan, W; Kos, I; Batinic-Haberle, I; Jones, S; Riggins, GJ; Friedman, H; Friedman, A; Reardon, D; Herndon, J; Kinzler, KW; Velculescu, VE; Vogelstein, B; Bigner, DD. IDH1 and IDH2 mutations in gliomas. New England Journal of Medicine. 2009;360:765-773.  Abstract
  • Parsons, DW; Jones, S; Zhang, X; Lin, JC; Leary, RJ; Angenendt, P; Mankoo, P; Carter, H; Siu, IM; Gallia, GL; Olivi, A; McLendon, R; Rasheed, BA; Keir, S; Nikolskaya, T; Nikolsky, Y; Busam, DA; Tekleab, H; Diaz, LA; Hartigan, J; Smith, DR; Strausberg, RL; Marie, SK; Shinjo, SM; Yan, H; Riggins, GJ; Bigner, DD; Karchin, R; Papadopoulos, N; Parmigiani, G; Vogelstein, B; Velculescu, VE; Kinzler, KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008;321:1807-1812.  Abstract
  • Di, C; Liao, S; Adamson, DC; Parrett, TJ; Broderick, DK; Shi, Q; Lengauer, C; Cummins, JM; Velculescu, VE; Fults, DW; McLendon, RE; Bigner, DD; Yan, H. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Research. 2005;65:919-924.  Abstract
  • Broderick, DK; Di, C; Parrett, TJ; Samuels, YR; Cummins, JM; McLendon, RE; Fults, DW; Velculescu, VE; Bigner, DD; Yan, H. Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Research. 2004;64:5048-5050.  Abstract
  • Samuels, Y; Wang, Z; Bardelli, A; Silliman, N; Ptak, J; Szabo, S; Yan, H; Gazdar, A; Powell, SM; Riggins, GJ; Willson, JK; Markowitz, S; Kinzler, KW; Vogelstein, B; Velculescu, VE. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554.  Abstract
  • Wang, Z; Shen, D; Parsons, DW; Bardelli, A; Sager, J; Szabo, S; Ptak, J; Silliman, N; Peters, BA; van der Heijden, MS; Parmigiani, G; Yan, H; Wang, TL; Riggins, G; Powell, SM; Willson, JK; Markowitz, S; Kinzler, KW; Vogelstein, B; Velculescu, VE. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science. 2004;304:1164-1166.  Abstract
  • Dressman, D; Yan, H; Traverso, G; Kinzler, KW; Vogelstein, B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proceedings of the National Academy of Sciences of USA. 2003;100:8817-8822.  Abstract
  • Yan, H; Dobbie, Z; Gruber, SB; Markowitz, S; Romans, K; Giardiello, FM; Kinzler, KW; Vogelstein, B. Small changes in expression affect predisposition to tumorigenesis. Nature Genetics. 2002;30:25-26.  Abstract
  • Yan, H; Yuan, W; Velculescu, VE; Vogelstein, B; Kinzler, KW. Allelic variation in human gene expression. Science. 2002;297:1143.  Abstract
  • Yan, H; Kinzler, KW; Vogelstein, B. Tech.sight. Genetic testing--present and future. Science. 2000;289:1890-1892.  Abstract
  • Yan, H; Papadopoulos, N; Marra, G; Perrera, C; Jiricny, J; Boland, CR; Lynch, HT; Chadwick, RB; de la Chapelle, A; Berg, K; Eshleman, JR; Yuan, W; Markowitz, S; Laken, SJ; Lengauer, C; Kinzler, KW; Vogelstein, B. Conversion of diploidy to haploidy. Nature. 2000;403:723-724.  Abstract