Hai Yan

Overview:

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.

Positions:

Henry S. Friedman Distinguished Professor of Neuro-Oncology in the School of Medicine

Pathology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1991

Beijing Medical University (China)

Ph.D. 1997

Columbia University

Research Associate, Howard Hughes Institute

Johns Hopkins University

Publications:

TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.

Diffuse intrinsic pontine gliomas (DIPGs) are high-grade tumors of the brainstem that often occur in children, with a median overall survival of less than one year. Given the fact that DIPGs are resistant to chemotherapy and are not amenable to surgical resection, it is imperative to develop new therapeutic strategies for this deadly disease. The p53 pathway is dysregulated by TP53 (~ 60%) or PPM1D gain-of-function mutations (~ 30%) in DIPG cases. PPM1D gain-of-function mutations suppress p53 activity and result in DIPG tumorigenesis. While MDM2 is a major negative regulator of p53, the efficacy of MDM2 inhibitor has not been tested in DIPG preclinical models. In this study, we performed a comprehensive validation of MDM2 inhibitor RG7388 in patient-derived DIPG cell lines established from both TP53 wild-type/PPM1D-mutant and TP53 mutant/PPM1D wild-type tumors, as well in TP53 knockout isogenic DIPG cell line models. RG7388 selectively inhibited the proliferation of the TP53 wild-type/PPM1D mutant DIPG cell lines in a dose- and time-dependent manner. The anti-proliferative effects were p53-dependent. RNA-Seq data showed that differential gene expression induced by RG7388 treatment was enriched in the p53 pathways. RG7388 reactivated the p53 pathway and induced apoptosis as well as G1 arrest. In vivo, RG7388 was able to reach the brainstem and exerted therapeutic efficacy in an orthotopic DIPG xenograft model. Hence, this study demonstrates the pre-clinical efficacy potential of RG7388 in the TP53 wild-type/PPM1D mutant DIPG subgroup and may provide critical insight on the design of future clinical trials applying this drug in DIPG patients.
Authors
Xu, C; Liu, H; Pirozzi, CJ; Chen, LH; Greer, PK; Diplas, BH; Zhang, L; Waitkus, MS; He, Y; Yan, H
MLA Citation
Xu, Cheng, et al. “TP53 wild-type/PPM1D mutant diffuse intrinsic pontine gliomas are sensitive to a MDM2 antagonist.Acta Neuropathol Commun, vol. 9, no. 1, Nov. 2021, p. 178. Pubmed, doi:10.1186/s40478-021-01270-y.
URI
https://scholars.duke.edu/individual/pub1500632
PMID
34732238
Source
pubmed
Published In
Acta Neuropathologica Communications
Volume
9
Published Date
Start Page
178
DOI
10.1186/s40478-021-01270-y

Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer.

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.
Authors
Lee, DD; Komosa, M; Sudhaman, S; Leão, R; Zhang, CH; Apolonio, JD; Hermanns, T; Wild, PJ; Klocker, H; Nassiri, F; Zadeh, G; Diplas, BH; Yan, H; Gallinger, S; Pugh, TJ; Ramaswamy, V; Taylor, MD; Castelo-Branco, P; Nunes, NM; Tabori, U
MLA Citation
Lee, Donghyun D., et al. “Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer.J Clin Invest, vol. 131, no. 21, Nov. 2021. Pubmed, doi:10.1172/JCI146915.
URI
https://scholars.duke.edu/individual/pub1500939
PMID
34720085
Source
pubmed
Published In
J Clin Invest
Volume
131
Published Date
DOI
10.1172/JCI146915

The implications of IDH mutations for cancer development and therapy.

Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.
Authors
MLA Citation
Pirozzi, Christopher J., and Hai Yan. “The implications of IDH mutations for cancer development and therapy.Nat Rev Clin Oncol, vol. 18, no. 10, Oct. 2021, pp. 645–61. Pubmed, doi:10.1038/s41571-021-00521-0.
URI
https://scholars.duke.edu/individual/pub1486137
PMID
34131315
Source
pubmed
Published In
Nature Reviews. Clinical Oncology
Volume
18
Published Date
Start Page
645
End Page
661
DOI
10.1038/s41571-021-00521-0

Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies.

Isocitrate dehydrogenase (IDH) active-site mutations cause a neomorphic enzyme activity that results in the formation of supraphysiologic concentrations of D-2-hydroxyglutarate (D-2HG). D-2HG is thought to be an oncometabolite that drives the formation of cancers in a variety of tissue types by altering the epigenetic state of progenitor cells by inhibiting enzymes involved in histone and DNA demethylation. This model has led to the development of pharmacologic inhibitors of mutant IDH activity for anticancer therapy, which are now being tested in several clinical trials. Emerging evidence in preclinical glioma models suggests that the epigenetic changes induced by D-2HG may persist even after mutant IDH activity is inhibited and D-2HG has returned to basal levels. Therefore, these results have raised questions as to whether the exploitation of downstream synthetic lethal vulnerabilities, rather than direct inhibition of mutant IDH1, will prove to be a superior therapeutic strategy. In this review, we summarize the preclinical evidence in gliomas and other models on the induction and persistence of D-2HG-induced hypermethylation of DNA and histones, and we examine emerging lines of evidence related to altered DNA repair mechanisms in mutant IDH tumors and their potential for therapeutic exploitation.
Authors
MLA Citation
Waitkus, Matthew S., and Hai Yan. “Targeting Isocitrate Dehydrogenase Mutations in Cancer: Emerging Evidence and Diverging Strategies.Clin Cancer Res, vol. 27, no. 2, Jan. 2021, pp. 383–88. Pubmed, doi:10.1158/1078-0432.CCR-20-1827.
URI
https://scholars.duke.edu/individual/pub1459997
PMID
32883741
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
383
End Page
388
DOI
10.1158/1078-0432.CCR-20-1827

Hitting Gliomas When They Are Down: Exploiting IDH-Mutant Metabolic Vulnerabilities.

Tumors mutated in IDH1 tend to have lower levels of the essential substrate NAD+. In this issue of Cancer Discovery, Nagashima and colleagues exploit this metabolic sensitivity by devising a combinatorial therapy that both further reduces the pools as well as sequesters the remaining substrate in PAR chains, sensitizing the cells to temozolomide and PARG inhibition.See related article by Nagashima et al., p. 1672.
Authors
MLA Citation
Pirozzi, Christopher J., and Hai Yan. “Hitting Gliomas When They Are Down: Exploiting IDH-Mutant Metabolic Vulnerabilities.Cancer Discov, vol. 10, no. 11, Nov. 2020, pp. 1629–31. Pubmed, doi:10.1158/2159-8290.CD-20-1215.
URI
https://scholars.duke.edu/individual/pub1464393
PMID
33139340
Source
pubmed
Published In
Cancer Discov
Volume
10
Published Date
Start Page
1629
End Page
1631
DOI
10.1158/2159-8290.CD-20-1215

Research Areas:

Adaptor Proteins, Signal Transducing
Adenocarcinoma
Adenocarcinoma, Clear Cell
Adenoma
Adenosine Triphosphatases
Adenosine Triphosphate
Adipates
Aged
Aged, 80 and over
Alcohol Oxidoreductases
Alleles
Alternative Splicing
Amino Acid Sequence
Animals
Annexin A5
Anoxia
Antibodies
Antibodies, Monoclonal
Antigens, CD4
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Arginine
Astrocytes
Astrocytoma
Base Pair Mismatch
Benzeneacetamides
Binding Sites
Blotting, Western
Brain Neoplasms
Burkitt Lymphoma
CD4 Antigens
Calpain
Carcinoma, Neuroendocrine
Carcinoma, Non-Small-Cell Lung
Carcinoma, Small Cell
Carcinoma, Squamous Cell
Carmustine
Catalytic Domain
Cell Differentiation
Cell Division
Cell Growth Processes
Cell Line
Cell Line, Transformed
Cell Line, Tumor
Cell Nucleus
Cell Proliferation
Cell Transformation, Neoplastic
Cells, Cultured
Central Nervous System Neoplasms
Cerebellar Neoplasms
Cerebellum
Chromatin
Chromatin Assembly and Disassembly
Chromatin Immunoprecipitation
Chromosome Aberrations
Chromosome Painting
Chromosomes
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 19
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 9
Cloning, Molecular
Codon
Codon, Nonsense
Cohort Studies
Colon
Colorectal Neoplasms
Computational Biology
CpG Islands
Cyclin-Dependent Kinase Inhibitor p18
Cytoplasm
DNA
DNA Copy Number Variations
DNA Helicases
DNA Methylation
DNA Mutational Analysis
DNA Primers
DNA Probes
DNA Repair
DNA, Complementary
DNA, Neoplasm
Dioxygenases
Dipeptides
Disease Progression
Dogs
Down-Regulation
Drug Resistance, Neoplasm
Endoplasmic Reticulum
Energy Metabolism
Enzyme Induction
Enzyme Inhibitors
Epigenesis, Genetic
Epigenomics
Escherichia coli
Exons
Female
Fibrosarcoma
Flow Cytometry
Fluorescent Dyes
Frameshift Mutation
Gene Amplification
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Gene Silencing
Genes, APC
Genes, Neoplasm
Genes, Reporter
Genes, Tumor Suppressor
Genes, erbB-1
Genes, myc
Genetic Complementation Test
Genetic Loci
Genetic Techniques
Genetic Variation
Genetics, Medical
Genome, Human
Genome-Wide Association Study
Genomics
Genotype
Germ-Line Mutation
Glioblastoma
Glioma
Glucose
Glutarates
Glutathione Transferase
Guanylate Cyclase
HCT116 Cells
Hematopoiesis
Histidine
Histone-Lysine N-Methyltransferase
Histones
Homeodomain Proteins
Humans
Hybridomas
Hypoxia
Hypoxia-Inducible Factor 1
Imidazoles
Immunoblotting
Immunohistochemistry
Immunoprecipitation
In Situ Hybridization, Fluorescence
Interferon Type I
Interferon-alpha
Interferon-gamma
Isocitrate Dehydrogenase
Isocitrates
Janus Kinase 1
Kaplan-Meier Estimate
Karyotyping
Ketoglutaric Acids
Kruppel-Like Transcription Factors
Lactates
Leukemia, Myeloid, Acute
Ligands
Loss of Heterozygosity
Lymphocytes
Magnetics
Male
Medulloblastoma
Melanoma
Metabolome
Methylation
Methylene Blue
Mice
Mice, Inbred BALB C
Mice, Nude
Mice, Transgenic
MicroRNAs
Microsatellite Instability
Microsatellite Repeats
Microtubule-Associated Proteins
Middle Aged
Models, Biological
Models, Molecular
Molecular Sequence Data
Moths
MutS Homolog 2 Protein
Mutagenesis, Site-Directed
Mutant Proteins
Mutation
Mutation, Missense
Neoplasm Grading
Neoplasm Transplantation
Neoplasms
Neoplasms, Experimental
Neural Stem Cells
Oligodendroglioma
Oncogenes
Otx Transcription Factors
Phenotype
Phenylurea Compounds
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Phosphotyrosine
Physical Chromosome Mapping
Point Mutation
Polymerase Chain Reaction
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Procollagen-Proline Dioxygenase
Prognosis
Promoter Regions, Genetic
Protein Biosynthesis
Protein Conformation
Protein Engineering
Protein Kinases
Protein Processing, Post-Translational
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 13
Protein Tyrosine Phosphatase, Non-Receptor Type 3
Protein Tyrosine Phosphatases
Protein-Tyrosine Kinases
Proto-Oncogene Proteins
RNA Interference
RNA, Messenger
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Receptor Protein-Tyrosine Kinases
Receptor, Epidermal Growth Factor
Receptor, Interferon alpha-beta
Receptor, Notch2
Receptor, trkC
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Receptors, Cell Surface
Receptors, Cytokine
Receptors, Interferon
Recombinant Fusion Proteins
Repressor Proteins
Reverse Transcriptase Polymerase Chain Reaction
Rhombencephalon
Risk Factors
S100 Proteins
STAT1 Transcription Factor
STAT2 Transcription Factor
Saccharomyces cerevisiae
Sequence Analysis, DNA
Sequence Deletion
Signal Transduction
Spodoptera
Stomach
Stomach Neoplasms
Streptolysins
Sulfonamides
Suppressor of Cytokine Signaling Proteins
Survival Rate
TYK2 Kinase
Telomerase
Telomere
Templates, Genetic
Tolonium Chloride
Trans-Activators
Transcription, Genetic
Transfection
Tretinoin
Tumor Cells, Cultured
Tumor Markers, Biological
Tumor Stem Cell Assay
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Tunicamycin
Tyrosine
Up-Regulation
Xenograft Model Antitumor Assays
Young Adult
src Homology Domains