1. Cancer Bioinformatics Tom Doman Bioinformatics Scientist Eli Lilly & Company Informatics 519 guest lecture IU Bloomington Sept-11-2013

2. Cancer Facts & Figures Leading cause of death among Americans under age 85 (surpassed heart disease in 1999) 200+ different types affecting 60+ different organs

3. Genes and Cancer Chromosomes are DNA molecules Heredity Radiation Chemicals Viruses

4. DNA Mutation Additions Deletions Normal gene Single base change DNA C T AGCGAACTAC AGGCGCTAACACT AGCTAACTAC AGAACTAC

5. Oncogenes Mutated/damaged oncogene Oncogenes accelerate cell growth and division Cancer cell Normal cell Normal genes regulate cell growth

6. Tumor Suppressor Genes Normal genes prevent cancer Remove or inactivate tumor suppressor genes Mutated/inactivated tumor suppressor genes Damage to both genes leads to cancer Cancer cell Normal cell

7. Tumor Suppressor Genes Act Like a Brake Pedal Tumor Suppressor Gene Proteins DNA Cell nucleus Signaling enzymes Growth factor Receptor Transcription factors Cell proliferation

8. p53 Tumor Suppressor Protein Triggers Cell Suicide Normal cellCell suicide (Apoptosis) p53 protein Excessive DNA damage

9. DNA Repair Genes Cancer No cancer No DNA repair Normal DNA repair Base pair mismatch TCATC AGTCG TCAGC AGTCG AGTGAGTAG TCATCTCATC

10. Cancer Tends to Involve Multiple Mutations Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites More mutations, more genetic instability, metastatic disease Proto-oncogenes mutate to oncogenes Mutations inactivate DNA repair genes Cells proliferate Mutation inactivates suppressor gene Benign tumor cells grow only locally and cannot spread by invasion or metastasis Time

11. Mutations and Cancer Genes Implicated in Cancer

12. Cancer Tends to Corrupt Surrounding Environment Growth factors = proliferation Blood vessel Proteases Cytokines Matrix Fibroblasts, adipocytes Invasive Cytokines, proteases = migration & invasion

13. Hallmarks of cancer Hanahan, D.; Weinberg, R. Cell Volume 100, Issue 1, 7 January 2000, Pages 57–70 Cell Volume 100, Issue 1, 7 January 2000, Pages 57–70

14. Hallmarks of cancer: the next generation Hanahan, D.; Weinberg, R. Cell, 2011, Vol. 144, #5, pp. 646-674. Cell, 2011, Vol. 144, #5, pp. 646-674

15. Hallmarks of cancer: the next generation Hanahan, D.; Weinberg, R. Cell, 2011, Vol. 144, #5, pp. 646-674. Cell, 2011, Vol. 144, #5, pp. 646-674

16. Cancer research relies intensively & increasingly on bioinformatics Gene mutation DNA copy number mRNA expresion Epigenetics: miRNA, DNA methylation / chromatin remodeling Protein levels PTM / splice variation / etc. Pathways

17. Understanding genetic lesions that drive cancer TERT amplification Chromothripsis on chr 11? HeLa cells / PICNIC / full genome plot HPV integration

18. Molecular correlates of patient survival involve metabolic pathways CJ Creighton et al. Nature vol. 499, #7456 pp. 43-49 (2013)

19. Challenges in Cancer Metastatic / disseminated disease Solid tumors (carcinomas / epithelial) Control / direct immune system Understand differences in cancer susceptibility –Peto’s Paradox –Naked mole rat –Tumor suppressor dynamics in different populations Epigenetics