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Tumor genetics Minna Thullberg minna.thullberg@labmed.ki.se
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Basic concepts of carcinogenesis
Cancer is a disease of the genes Phenotypes of cancer cells What is an oncogene Break What is a tumor suppressor gene Inherited versus sporadic cancer The molecular pathway concept Discussion and microarray Summary of the most important stuff
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G0 (t) Cells in arrest G0 (i) M G1 G2 X R S Cells in the cell cycle
Terminally differentiated Do not form tumors Cells in arrest G0 (i) Latent ability to regenerate Form tumors occasionally G1 G2 S M X R nucleus cell chromosomes Dividing cells Form tumors with highest frequency Cells in the cell cycle
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Cancer is a genetic disease which develops stepwise
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Vogelstein 1990 Normal epithelium Hyperprolifer - ating epithelium
Early adenoma Intermediate Late Carcinoma Metastasis Chromosome : Alteration: Gene: 5q mut . or loss APC DNA hypo methylation 12p K-ras 18q loss DCC 17p p53 other alterations Vogelstein 1990
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Chernoff J
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Phenotypes of cells in a tumor
Loss of Differentiation Increased Proliferation Heterogeneity All tumors seem to be different
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Common characteristics of cancer cells
Increased cell proliferation due to * Growth without growth factors * Insensitivity to growth inhibitors Resistance to apoptosis (committed cell death) Indefinite lifespan= limitless replicative potential Genetic instability due to e.g. Protection against apoptosis or defect DNA repair Sustained angiogenesis In the invasive tumor Tissue invasion metastasis
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Proliferation Growth stimulation Growth inhibition Adhesion
e.g. Growth factors e.g. Growth inhibitors Growth factor receptors Growth inhibitor receptors GTPases Adhesion kinases e.g. Extracellular matrix Cell-cell contact GTPases Signal transduction Contact receptors kinases Gene transcription Transcription factors Contact inhibition Cell-cell contact
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Cellular response of STRESS
Arrest or Apoptosis Cellular response of STRESS Intracellular stress Extracellular stress Protease cascade apoptosis HEAT caspase DNA damage Chemical imbalance caspase Cell cycle arrest Cytokines Ca2+ concentration Stress receptor Stress sensor p53 ATM P53 and/or ATM trigger arrest or apoptosis upon DNA damage
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Parslow M
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Telomeres protect the end of chromosomes
Telomere tandem Parslow M
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Stem cells and most cancer cells express TELOMERASE
The telomeres get shorter for each round of replication Until a certain limit when the cell stops to divide Cell division with too short telomeres induces gene instability Stem cells and most cancer cells express TELOMERASE an enzyme which synthesize telomeres and induces unlimited life-span
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What is an oncogene? Induces transformation
Induces proliferation Induces transformation or Induces resistance to apoptosis Upregulated in human tumors A Proto-oncogene can become an oncogene by a genetic change Viral oncogenes (HPV)
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Proto-oncogenes are: Growth factors Growth factor receptors
Signal transduction proteins (kinases, G-proteins) Transcription factors Cell cycle proteins Inhibitors of apoptosis Telomerase?
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Proliferation Growth stimulation Growth inhibition Adhesion
e.g. Growth factors e.g. Growth inhibitors Growth factor receptors Growth inhibitor receptors GTPases Adhesion kinases e.g. Extracellular matrix Cell-cell contact GTPases Signal transduction Contact receptors kinases Gene transcription Transcription factors Contact inhibition Cell-cell contact
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Proto-oncogenes are transformed into oncogenes by:
Activating mutations Translocations Transactivation Gene amplification Integration of virus
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Genetic changes can be triggered by
From living: DNA replication Metabolism creating reactive metabolites Stress from outside: UV light, smoking, chemicals
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A Tumor suppressor is normally controlling cell growth or apoptosis
And is lost or inactivated in cancer
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Tumor suppressor Normal situation 2 alleles functional proteins mother
father mother functional proteins 2 alleles
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Tumor suppressor 2 genetic hits NO functional proteins disease
Inherited or spontaneous genetic change mother father mutation defect proteins functional proteins 2 genetic hits only defect proteins gene deletion NO functional proteins disease Further genetic change in the second allele
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Mechanisms of tumor suppressor gene inactivation
Inactivating mutations Gene deletions Viral oncogenes Promotor silencing
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Viral oncogenes e g in HPV express proteins
which bind and inactivate p53 and pRb two guards of apoptosis and cell proliferation Changes in the structure of a gene’s promotor can lead to silencing of that gene and no protein will be expressed
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Inherited cancer Inherited predisposition for tumor disease
occurs typically through a mutation in a tumor suppressor gene The tumor develops when the second allele is also deleted or inactivated. In spontaneous developed tumors there need to be two hits in the tumor suppressor genes Which take longer time
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Examples of inherited cancer ”syndromes”
Retinoblastom(retina) pRb cell cycle control Polyposis Coli (colon) APC differentiation Ataxia Telangiectasi (general) ATM DNA repair Breast Cancer BRCA1, BRCA2 DNA repair Melanoma p16 cell cycle
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The Cell Cycle G0 nucleus cell M chromosomes G1 G2 X R S
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G0 M G2 G1 R X S Cyclin B-CDC2 p16 Cyclin A-CDC2 Cyclin D-CDK4
Cyclin E-CDK2 Cyclin A-CDK2
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Rb Rb p16 cyclin D cdk 4/6 -Gene amplification
-Chromosomal rearrangement - Proviral integration -Protein stabilisation -Gene deletion -Inactivating mutations - Promotor silencing by DNA methylation p16 cyclin D cdk 4/6 -Gene amplification -Loss of p16 binding -Gene deletion -Loss of function mutations -Functional inactivation by viral oncoproteins P P P Rb Rb
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Hanahan and Weinberg, Cell, 2000
As for the genetic reprogramming of this integrated circuit in cancer cells, some of the genes known to be functionally altered are highlighted in red. Hanahan and Weinberg, Cell, 2000
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Summary Cancer develops stepwise through genetic changes
Several genes are affected and it seems like all tumors are different An oncogene promote tumor growth A tumor suppressor normally control cell growth, or apoptosis but it is functionally lost in tumors
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Common characteristics of cancer cells
Increased cell proliferation due to * Growth without growth factors * Insensitivity to growth inhibitors Resistance to apoptosis (committed cell death) Indefinite lifespan= limitless replicative potential Genetic instability due to e.g. Protection against apoptosis or defect DNA repair Sustained angiogenesis In the invasive tumor Tissue invasion metastasis
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