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Session 1.5: Belbin
 

Session 1.5: Belbin

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Tom Belbin

Tom Belbin

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    Session 1.5: Belbin Session 1.5: Belbin Presentation Transcript

    • New Epigenetic Biomarkers of Oropharyngeal Cancer
      Thomas J. Belbin
      Department of Pathology
      5/21/2010
      Science at the heart of medicine
    • 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
    • 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.
    • DNA methylation in cancer
      5/21/2010
      Science at the heart of medicine
    • HumanMethylation27 Content Summary
      5/21/2010
      Science at the heart of medicine
    • 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)
    • Differential DNA methylation in OPSCC
      5/21/2010
      Science at the heart of medicine
    • 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
    • 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.
    • 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.
    • 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 .
    • Executive Report
      5/21/2010
      Clinically relevant biomarkers
    • 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
    • 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
      • a distant metastasis
      • treatment for persistent disease
      • died of disease
      • 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.
    • 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
    • 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)