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Tumor genetics Minna Thullberg [email protected] 08-585 87985 Basic concepts of carcinogenesis Cancer is a disease of the genes Phenotypes of cancer cells What is an oncogene What is a tumor suppressor gene Inherited versus sporadic cancer The molecular pathway concept Discussion and microarray Summary of the most important stuff Break Cells in arrest G0 (t) Terminally differentiated G0 (i) Latent ability to regenerate Do not form tumors Form tumors occasionally nucleus M G2 cell chromosomes G1 X S Cells in the cell cycle R Dividing cells Form tumors with highest frequency Cancer is a geneticMultistep disease which develops stepwise carcinogenesis normal cells genetic change clonal expansion genetic change invasive tumor clonal expansion genetic change Chromosome 5q : Alteration: . mut or loss Gene: APC 12p mut K-ras . 18q loss DCC 17p loss p53 DNA hypo methylation Normal epithelium Hyperprolifer ating epithelium Early adenoma other alterations Intermediate adenoma Vogelstein 1990 Late adenoma Carcinoma Metastasis TRANS FO RMED C ELLS Di vi de wh e n th e y sh ou l dn 't loss of serum dependence loss of contact inhibition loss of anchorage dependence Abn orm al sh ape Chernoff J Phenotypes of cells in a tumor Loss of Differentiation Increased Proliferation Heterogeneity All tumors seem to be different 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 Tissue invasion metastasis In the invasive tumor Proliferation Growth stimulation Growth inhibition e.g. Growth factors e.g. Growth inhibitors Growth factor receptors Growth inhibitor receptors GTPases kinases Adhesion e.g. Extracellular matrix GTPases Cell-cell contact Contact receptors Signal transduction kinases Gene transcription Transcription factors Contact inhibition Cell-cell contact Arrest or Apoptosis Cellular response of STRESS Intracellular stress Extracellular stress Protease cascade apoptosis caspase HEAT DNA damage Chemical imbalance caspase Cytokines Cell cycle arrest Ca2+ concentration Stress receptor Stress sensor p53 ATM P53 and/or ATM trigger arrest or apoptosis upon DNA damage Parslow M Telomeres protect the end of chromosomes Telomere tandem Parslow M 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 What is an oncogene? Induces proliferation or Induces resistance to apoptosis Induces transformation Upregulated in human tumors A Proto-oncogene can become an oncogene by a genetic change Viral oncogenes (HPV) Proto-oncogenes are: Growth factors Growth factor receptors Signal transduction proteins (kinases, G-proteins) Transcription factors Cell cycle proteins Inhibitors of apoptosis Telomerase? Proliferation Growth stimulation Growth inhibition e.g. Growth factors e.g. Growth inhibitors Growth factor receptors Growth inhibitor receptors GTPases kinases Adhesion e.g. Extracellular matrix GTPases Cell-cell contact Contact receptors Signal transduction kinases Gene transcription Transcription factors Contact inhibition Cell-cell contact Proto-oncogenes are transformed into oncogenes by: Activating mutations Translocations Transactivation Gene amplification Integration of virus Genetic changes can be triggered by From living: DNA replication Metabolism creating reactive metabolites Stress from outside: UV light, smoking, chemicals A Tumor suppressor is normally controlling cell growth or apoptosis And is lost or inactivated in cancer Tumor suppressor Normal situation mother father 2 alleles functional proteins Tumor suppressor Inherited or spontaneous genetic change mother mutation father defect proteins functional proteins Further genetic change in the second allele gene deletion 2 genetic hits only defect proteins NO functional proteins disease Mechanisms of tumor suppressor gene inactivation Inactivating mutations Gene deletions Viral oncogenes Promotor silencing 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 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 Examples of inherited cancer ”syndromes” Retinoblastom(retina) pRb Polyposis Coli (colon) APC Ataxia Telangiectasi (general)ATM Breast Cancer Melanoma cell cycle control differentiation DNA repair BRCA1, BRCA2 p16 DNA repair cell cycle The Cell Cycle G0 nucleus cell M chromosomes G1 G2 X S R Cyclin B-CDC2 Cyclin A-CDC2 G0 M p16 G1 G2 R Cyclin D-CDK4 X Cyclin D-CDK6 S Cyclin E-CDK2 Cyclin A-CDK2 -Gene amplification -Chromosomal rearrangement -Proviral integration -Protein stabilisation -Gene deletion -Inactivating mutations -Promotor silencing by DNA methylation p16 cyclin D cdk 4/6 -Gene deletion -Loss of function mutations -Functional inactivation by viral oncoproteins -Gene amplification -Loss of p16 binding P Rb P P Rb 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. 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 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 Tissue invasion metastasis In the invasive tumor