Medical Genetics & Genomics Guri Tzivion, PhD
[email protected] 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
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