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Cancer Bioinformatics Tom Doman Bioinformatics Scientist Eli Lilly & Company Informatics 519 guest lecture IU Bloomington Sept-11-2013 Cancer Facts & Figures • Leading cause of death among Americans under age 85 (surpassed heart disease in 1999) • 200+ different types affecting 60+ different organs Genes and Cancer Viruses Chemicals Radiation Heredity Chromosomes are DNA molecules DNA Mutation DNA CA AG C T A A C T Normal gene CA AG C G A A C T Single base change CA A G G CG C T A A C T Additions C T CA A G A A C T Deletions Oncogenes Normal cell Cancer cell Mutated/damaged oncogene Normal genes regulate cell growth Oncogenes accelerate cell growth and division Tumor Suppressor Genes Normal genes prevent cancer Normal cell Remove or inactivate tumor suppressor genes Cancer cell Damage to both genes leads to cancer Mutated/inactivated tumor suppressor genes Tumor Suppressor Genes Act Like a Brake Pedal Tumor Suppressor Gene Proteins Growth factor Receptor Signaling enzymes Cell nucleus Transcription factors DNA Cell proliferation p53 Tumor Suppressor Protein Triggers Cell Suicide p53 protein Normal cell Excessive DNA damage Cell suicide (Apoptosis) DNA Repair Genes Normal DNA repair T C GA C Base pair mismatch No cancer TC T AC AG C T G TC TAC TCT AC AG C T G Cancer AG TG AG A T G No DNA repair Cancer Tends to Involve Multiple Mutations Benign tumor cells grow only locally and cannot spread by invasion or metastasis Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Mutation Cells inactivates proliferate suppressor gene Mutations inactivate DNA repair genes Proto-oncogenes mutate to oncogenes More mutations, more genetic instability, metastatic disease Mutations and Cancer Genes Implicated in Cancer Cancer Tends to Corrupt Surrounding Environment Growth factors = proliferation Invasive Matrix Proteases Fibroblasts, adipocytes Blood vessel Cytokines, proteases = migration & invasion Cytokines Hallmarks of cancer Hanahan, D.; Weinberg, R. Cell Volume 100, Issue 1, 7 January 2000, Pages 57–70 Hallmarks of cancer: the next generation Hanahan, D.; Weinberg, R. Cell, 2011, Vol. 144, #5, pp. 646-674. Hallmarks of cancer: the next generation Hanahan, D.; Weinberg, R. Cell, 2011, Vol. 144, #5, pp. 646-674. 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 Understanding genetic lesions that drive cancer HeLa cells / PICNIC / full genome plot HPV integration TERT amplification Chromothripsis on chr 11? Molecular correlates of patient survival involve metabolic pathways CJ Creighton et al. Nature vol. 499, #7456 pp. 43-49 (2013) 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
