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Session 1.5 Belbin

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Tom Belbin

Tom Belbin

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  • 1. New Epigenetic Biomarkers of Oropharyngeal Cancer
    Thomas J. Belbin
    Department of Pathology
    5/21/2010
    Science at the heart of medicine
  • 2. 5/21/2010
    Science at the heart of medicine
    Head and Neck Squamous Cell Carcinoma
    >48K cases, >11K deaths in the US
    oral cavity, oropharynx, hypopharynx, larynx, nasopharynx
    tobacco, alcohol, HPV, betel quid etc.
    surgery, radiation, chemotherapy
    recurrence in about 50% of patients
    5-year survival rate (~50%)
    no molecular markers
  • 3. Einstein/Montefiore Head and Neck Cancer Research Group
    5/21/2010
    Science at the heart of medicine
    Programmatic Goals:
    Predict tumor behavior
    Optimize treatment selection
    Identify potential new therapeutic targets
    Einstein Head and Neck Cancer Research Group: Belbin et al. (2007). Head and neck cancer: reduce and integrate for optimal outcome. Cytogenet Genome Res 118:92–109.
  • 4. DNA methylation in cancer
    5/21/2010
    Science at the heart of medicine
  • 5. HumanMethylation27 Content Summary
    5/21/2010
    Science at the heart of medicine
  • 6. Differential DNA methylation in OPSCC
    5/21/2010
    Science at the heart of medicine
    r2=0.96
    CpG loci within classically defined CpG island (20,007 loci)
    CpG loci outside of classically defined CpG island (7,572 loci)
  • 7. Differential DNA methylation in OPSCC
    5/21/2010
    Science at the heart of medicine
  • 8. Distribution of differentially methylated CpG loci on chromosomes 18. Data points are plotted as the average difference in beta between OPSCC tumor and normal mucosa for the 24 patients in Patient Set 1. Points above the ideogram are identified as hypermethylated in OPSCC; those below the ideogram are identified as hypomethylated.
    5/21/2010
    Science at the heart of medicine
  • 9. 5/21/2010
    Science at the heart of medicine
    Distribution of differentially methylated CpG loci on chromosomes 19. Data points are plotted as the average difference in beta between OPSCC tumor and normal mucosa for the 24 patients in Patient Set 1. Points above the ideogram are identified as hypermethylated in OPSCC; those below the ideogram are identified as hypomethylated.
  • 10. 5/21/2010
    Science at the heart of medicine
    Distribution of differentially methylated CpG loci on chromosomes 19. Data points are plotted as the average difference in beta between OPSCC tumor and normal mucosa for the 24 patients in Patient Set 1. Points above the ideogram are identified as hypermethylated in OPSCC; those below the ideogram are identified as hypomethylated.
  • 11. Can ZNF671 be pharmacologically re-expressed in a model system?
    5/21/2010
    Science at the heart of medicine
    FaDu
    manipulate expression and study phenotype
    study mechanism in a model system
    Belbin et al. (2010). Aberrant DNA Methylation of ZNF Family Nucleic Acid Binding Protein Genes on Chromosome 19 in Oropharyngeal Squamous Cell Carcinoma. Submitted to American Journal of Pathology .
  • 12. Executive Report
    5/21/2010
    Clinically relevant biomarkers
  • 13. A Computational Approach for HNSCC Biomarker Discovery
    5/21/2010
    Science at the heart of medicine
    N0
    N+
    N+
    N0
    Support Vector Machine (SVM): machine learning algorithm used to divide samples into predefined groups based on a set of attributes
  • 14. Signatures of DNA methylation are predictive of outcome in oropharyngeal squamous cell carcinoma
    5/21/2010
    Science at the heart of medicine
    Confusion matrices showing the performance of independent, feature selected SVM models trained to predict for aggressive disease status or nodal metastasis.
    150 CpG signature
    Aggressive Disease @ 24 months:
    • a recurring (local, regional) primary tumor
    • 15. a distant metastasis
    • 16. treatment for persistent disease
    • 17. died of disease
    • 18. 12 out of 36 OP patients
    Nodal metastasis at diagnosis (N+ vs N0)
    38 out of 51 OP patients
    125 CpG signature
    Lleras et al. (2010). Signatures of DNA methylation are predictive of outcome in head and neck squamous cell carcinoma. Manuscript in preparation.
  • 19. Future Directions
    Validate our predictive signatures in external patient populations to develop a clinically useful test for treatment selection at initial diagnosis.
    Test the functional significance of clinically relevant genes using the cell line model system.
    What about other anatomic sites?
    Can other –omics platforms be used to build prognostic signatures? (ex. gene expression, microRNA)
    5/21/2010
    Science at the heart of medicine
  • 20. Acknowledgements
    5/21/2010
    Science at the heart of medicine
    Albert Einstein College of Medicine
    (www.einstein.yu.edu)
    Dr. Michael Prystowsky
    Dr. Geoffrey Childs
    Dr. Nicolas Schlecht
    Dr. Thomas Harris
    Aldo Massimi
    Nicole Kawachi
    Leslie Adrien
    Roberto Lleras
    Xin Zheng
    Quan Chen
    Montefiore Medical Center
    (www.montefiore.org)
    Dr. Richard Smith
    Dr. Brad Schiff
    Dr. Margie Brandwein-Gensler
    Dr. Chris Keller
    Dr. Missak Haigentz
    Dr. Madhur Garg
    Cathy Sarta
    Supported by :
    NIH Grant # R21CA104402 (TJB)
    NIH Grant # R21CA131648 (TJB)
    NIH Grant # R33CA103547 (MBP)
    Thyroid Head and Neck Cancer (THANC) Foundation (TJB)