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Hai Yan

Professor of Pathology
Research Interest: 
Developmental biology
Molecular structure
Research Summary: 
Cancer genetics and therapy
Research Description: 

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.

IDH1 and IDH2 mutations in gliomas.
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.
N Engl J Med. 2009. 360:765-73.

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.
Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H.
Proc Natl Acad Sci U S A. 2011. 108:3270-5.

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation.
Duncan CG, Barwick BG, Jin G, Rago C, Kapoor-Vazirani P, Powell DR, Chi JT, Bigner DD, Vertino PM, Yan H.
Genome Res. 2012. 22:2339-55.

Enzyme redesign guided by cancer-derived IDH1 mutations.
Reitman ZJ, Choi BD, Spasojevic I, Bigner DD, Sampson JH, Yan H.
Nat Chem Biol. 2012. 8:887-9.

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.
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.
Oncotarget. 2012. 3:709-22.