Tom Belbin

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

15. a distant metastasis

16. treatment for persistent disease

17. died of disease

18. 12 out of 36 OP patientsNodal 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)