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Medical Genetics & Genomics Guri Tzivion, PhD tzivion@windsor.edu Extension 506 BCHM 560: January 2015 Windsor University School of Medicine

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Cancer types and classifications Carcinomas: epithelial origin involving the skin, mucous membranes, epithelial cells in glands etc. Sarcomas: cancer of connective tissue. Lymphomas: T or B cell, Hodgkins, Burkitts lymhomas. Can involve also solid tumors Leukemias: disseminated tumors - may be lymphoid or myeloid.

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Loss of Normal Growth Control Cancer cell division Fourth or later mutation Third mutation Second mutation First mutation Uncontrolled growth Cell Suicide or Apoptosis Cell damage no repair Normal cell division

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Oncogenesis proto-oncogenes tumor suppressor genes oncogenes carcinogen results in mutation dysfunctional tumor suppressor genes inherited defect increased GF increased GF receptors exaggerated response to GF loss of ability to repair damaged cells or induce apoptosis

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5 p53 is a common tumor suppressor mutated or deleted in nearly 50% of all human cancers

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Common traits of cancer cells Modified intercellular and intracellular signaling processes Increased proliferation rates Increased mobility of cells Increased invasive capabilities and ability to metastasize Ability to evade the immune system

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Carcinoma in Situ Mild dysplasia Carcinoma in situ (severe dysplasia) Cancer (invasive) NormalHyperplasia

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Cancer progression involves accumulation of 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

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Tumor Grading General Relationship Between Tumor Grade and Prognosis Patient Survival Rate Years High grade Low grade 100% 12345

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Tumor Staging Five-Year Survival Rates for Patients with Melanoma (by stage) Stage at Time of Initial Diagnosis 100% 50% IIIIII

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Other gene families implicated in cancer

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BCHM 560 MD2 Genetics Class 23 3. Cancer-2 BCHM 560 MD2 Genetics Class 23 Inherited genetic diseases 3. Cancer-2

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Molecular aspects of cancer pathogenesis: Oncogenes & Tumor Suppressors

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Oncogene definition/designation + oncogenes Oncogenes promote cell proliferation dominant & highly conserved types: viral oncogenes [v-oncs] cellular oncogenes [c-oncs] Proto-oncogene Mutation Oncogene

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Classes of Oncogenes A. Secreted Growth Factors B. Cell Surface Receptors C. Intracellular Transducers D. Transcription Factors E. Regulators of apoptosis Components of signal transduction pathways c-sis, hst erb B, fms, ret, trk, fes, fms c-src, c-abl, mst, ras myc, jun, fos bcl, bax, bad

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SIGNAL TRANSDUCTION

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The early 80s Black Box theory for signal transduction

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More current view of intracellular signaling cascades

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Mechanisms of GF signaling activation: 1. Receptor mutation or over- expression

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Mutations or deletions in GF receptors can result in constitutively active receptor forms

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Deletion of the ectodomain of EGFR results in a transforming viral gene

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Mechanisms of GF signaling activation: 2. Ligand over-expression

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Alternations in gene expression can provide autocrine loop, also resulting in constitutive activation of GF receptors

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Besides growth factor receptors, other types of extracellular domain-containing receptors have been found associated with cancer

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The Notch family of receptors

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The Jak-STAT pathway transmits signals form cytokine receptors directly to the nucleus

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Mechanisms of GF signaling activation: 3. Mutation in signaling molecules: a. The Ras-Raf-MAPK pathway

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Ras activation by Sos and Grb2

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Ras activation/inactivation cycle

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ONCOGENE FAMILY Mechanism of Ras Activation Point Mutation H-ras [codon 12] Normal: CGC Gly Bladder cancer: CTC Val H-rasV12 GTP Continuous cell division

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Ras-Raf-MAPK pathway activation

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Signaling pathways activated by Ras

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Mutations and protein-expression level variations of EGFR and the Ras pathway in human cancers

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Mechanisms of GF signaling activation: 3. Mutation in signaling molecules: b. The PI3K-PTEN-AKT pathway

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AKT activation process

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AKT activation and targets Life technologies

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Disease-associated AKT effectors Hers et al, Cellular Signaling 2011

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Adapted from: Porta & Figlin, J. Urology 182:2569-77, 2009

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Table 6.4 The Biology of Cancer ( Garland Science 2007)

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Mechanisms of GF signaling activation: 2. Over expression or activation of transcription factors

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Changes in gene expression profiles following serum stimulation

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Regulation of early-genes expression

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Therapeutics targeting GF receptors and downstream signaling pathways in cancer

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Targets for cancer therapy 1.Growth factors 2.Growth factor receptors 3.Adaptor proteins 4.Docking proteins/ binding proteins 5.Guanine nucleotide exchange factors 6.Phosphatases and phospholipases 7.Signaling kinases 8.Ribosomes 9.Transcription factors 10.Histones 11.Molecular chaperones 12.DNA 13.Microtubules 14.Cyclins 15.Cyclin-dependent kinases 16.Cell death receptors 17.Apoptosis-effector caspases 18.Caspase inhibitors 19.CD40-CD40L Cell Growth Motility Survival Proliferation Angiogenesis P P P P Growth Factor Signaling Gene Transcription DNA Replication and Repair 1 6358910 12 2 Plasma Membrane Nuclear Membrane 137 4 77 Microtubule Dynamics RNA Translation 14 15 161718 19 11

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Targeted Therapies Erlotinib Bevacizumab Sunitinib Sorafenib Chemotherapy Panitumumab Cetuximab Temsirolimus Inhibition of programmed cell death (apoptosis) Tumor cell proliferation Tumor cell invasion metastasis Development of tumor vasculature (angiogenesis)

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Inhibitors targeting the PI3K-AKT-mTOR pathway

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Signaling pathways activated by Ras: more complex than initially thought

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Complex interplay between ligands, receptors and intracellular signaling pathways coordinate the function of HER GF receptors

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The PI3-kinase pathway, generation of PIP 3