Pathology / Pathology Research

Duke Box 3156
Department of Pathology
Durham, NC 27710

(919) 668-7850

• MD, Beijing Medical University (p.r. China), 1991
• PhD, Columbia University, 1997

Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of novel genetic events involved in the genesis and progression of brain cancers. Through comprehensive elucidation of genetic alterations in brain tumors, we have revealed novel genes for diagnostic, prognostic, or therapeutic purposes, as well as subclassification of patients that may preferentially respond to particular targeted therapies.

Gliomas are the most common type of primary brain tumor. Through exome sequencing, we have identified mutations in the NADP+-dependent isocitrate dehydrogenases (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. Patients with IDH1 and IDH2 mutations represent a discrete group of glioma patients. Our long-term goal is to develop a novel molecular-based glioma classification system and a targeted therapy on the basis of IDH1 and IDH2 mutations, their partner genetic changes, such as TP53, ATRX, CIC and FUBP1, and the involved oncogenic and metabolic pathways. Studies involving cell line and animal models, enzymatic study, metabolome and epigenome, are being investigated to determine the consequences of IDH mutations on cancer cell development. Study of alterations in these metabolic enzymes may provide insights into the metabolism and epigenetic regulation of cancer cells and provide novel avenues for development of anticancer therapeutics.

http://cmb.duke.edu/research/faculty/hai-yanhttp://haiyanlab.com/

• 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