Molecular_Basis_of_cancer_2

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Molecular_Basis_of_cancer

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MOLECULAR BASIS OF CANCER Assoc.Prof. Işık G. Yuluğ Bilkent University Department of Molecular Biology and Genetics yulug@fen.bilkent.edu.tr: 

1 MOLECULAR BASIS OF CANCER Assoc.Prof. Işık G. Yuluğ Bilkent University Department of Molecular Biology and Genetics yulug@fen.bilkent.edu.tr

Cellular Basis of Cancer: 

2 Cellular Basis of Cancer Cancer is a collection of diseases characterized by abnormal and uncontrolled growth Cancer arises from a loss of normal growth control In normal tissues, the rates of new cell growth and old cell death are kept in balance In cancer, this balance is disrupted This disruption can result from 1) uncontrolled cell growth or 2) loss of a cell's ability to undergo apoptosis

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3 Cancer Cell Do Not Grow Faster Than Normal Cells Rather, Their Growth is Just Uncontrolled

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4 1 fertilized egg 50x10 12 Proliferation Differentiation Death 10 16 cell divisions/lifetime

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5 Proliferation Differentiation Death Transit Proliferating Exiting Renewing Cellular equilibrium

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6 Proliferation Differentiation Death Cancer: disruption of cellular equilibrium

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7 Post mitotic Stem cell Differentiated Normal senescent differentiated cell Benign tumor Grade 2 malignancy Grade 3 or 4 malignancy Stem cells as the target of carcinogens

Invasion and Metastasis : 

8 Invasion and Metastasis Abnormal cells proliferate and spread (metastasize) to other parts of the body Invasion - direct migration and penetration into neighboring tissues Metastasis - cancer cells penetrate into lymphatic system and blood vessels

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9 Benign tumors generally do not spread by invasion or metastasis Malignant tumors are capable of spreading by invasion and metastasis Malignant versus Benign Tumors

What causes Cancer?: 

10 What causes Cancer? Cancer is caused by alterations or mutations in the genetic code Can be induced in somatic cells by: Carcinogenic chemicals Radiation Some viruses Heredity - 5%

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11 Hanahan and Weinberg, Cell 100: 57, 2000 Apoptosis Oncogenes Tumor Suppressor Inv. and Mets Angiogenesis Cell cycle

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12 What is the molecular basis of cancer? Cancer is a gene tic disease. Mutations in genes result in altered proteins During cell division External agents Random event Most cancers result from mutations in somatic cells Some cancers are caused by mutations in germline cells

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13 Theories of cancer genesis Standard Dogma Proto-oncogenes (Ras – melanoma) Tumor suppressor genes (p53 – various cancers) Modified Dogma Mutation in a DNA repair gene leads to the accumulation of unrepaired mutations (xeroderma pigmentosum) Early-Instability Theory Master genes required for adequate cell reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome)

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14 CANCER AND GENETICS Cancer: genome disease Causes of genomic changes Effects of genomic changes Revolution in cancer treatment: ‘Smart Bullets Period’

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15 CANCER: GENOME DISEASE Loss of DNA Gain of DNA Changes in nucleotides Epigenetic effects

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16 Signs for Genomic Changes in Cancer Changes in chromosome numbers - Aneuploidy Chromosomal changes Increase in DNA copy number -15 different region - Loss in chromosomal - 200.000 regions Micro changes - Microsatellite changes Mikrosatellite - 100.000 - Nucleotide changes

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17

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18 Chromosomal changes in the genome of cancer cells: tip of the iceberg Terminal Deletion http://www.tokyo-med.ac.jp/genet/cai-e.htm Ring Chromosome Robertsonian Translocation Deletion Reciprocal translocation Isochromosomes Insertion Inversion Duplication

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19 Nucleotide changes in the genome of cancer cells: unseen site of the iceberg Nucleotide Deletions Nucleotide Insertions Nucleotide Substitutions http://www.tokyo-med.ac.jp/genet/cai-e.htm

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20 DNA Loss in cancer cells

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21 Early Brain Tumor ( Astrocytoma Stage II ) Advance Brain Tumor Gl i oblastoma Multiform ( Stage IV) DNA Loss in cancer cells : beyond coincidence . ..

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22 p53 locus Chromosomal loss: Mostly, it is a sign for the loss of a tumor suppressor gene PTEN locus CDKN2 locus RB1 locus ??? locus

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23 Cancer: Genome Disease Epigenetic effects

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24 Genetic and Epigenetic Silencing of Tumor Suppressor Genes Plass - 2002

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25 Carcinogenic chemicals UV Replication Errors Radiation Viruses Rearrangements (translocation, deletions, amplifications) Point mutations Alters DNA of genes controlling cell proliferation. (Proliferation becomes abnormal) Cancer cell Normal cell Damaged DNA THE CAUSES OF GENOMIC CHANGES IN CANCER

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26 Hasar Etken T ü r ü Hasar Etkeni Kanser Riski İşareti Fiziksel Mor ö tesi Işınlar Deri Ka., Melanoma P53 (CC-TT) Radyasyon Tiroid Ka., L ö semi Translokasyon Kimyasal Benzopren Akciğer Ka. p53 (G-T) Aflatoksin Karaciğer Ka. p53 (249 G-T) Oksidatif Stres Yaşlılık Kanserleri P53 (C-T) Biyolojik HBV Karaciğer Ka. Virus DNA İntegrasyonu THE CAUSES OF GENOMIC CHANGES IN CANCER: Somatic Changes

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27 Genes Disease Function Inheretance Cancer Risk FA Genes F-A DNA Damage respose ? OR L ö semi XP Genes X-P NER Type DNA Repair OR Skin Ca. BLM Bloom DNA Helicase ? OR Various cancers WRN Werner DNA Helicase ? OR Sarcoma RECQ4 Rothmund-Thomson DNA Helicase OR Sarcoma MLH1, MSH2, PMS1, PMS2 MMR DNA Repair OD Colon, Endometrium Ca. OR L ö semi, NF1 BRCA1, BRCA2 DNA Repair OD Breast, Ovary, Prostate, Pancreas Ca ATM A-T DNA Damage sense ? OR Lymphoma, Leukemia OD Breast Ca. ? p53 Li-Fraumeni DNA Damage sense OD Various cancers THE CAUSES OF GENOMIC CHANGES IN CANCER: Hereditary Predisposition

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28 Approximately 90-95% of all cancers are sporadic. 5-10% are inherited. CANCER AND GENETICS

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29 • Oncogenes • Tumor suppressor genes • DNA repair genes GENES PLAYING ROLE IN CANCER DEVELOPMENT

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30 What are the genes responsible for tumorigenic cell growth? Normal Cancer Proto-oncogenes Cell growth and proliferation Tumor suppressor genes + - Mutated or “activated” oncogenes Malignant transformation Loss or mutation of Tumor suppressor genes ++

ONCOGENES: 

31 ONCOGENES Oncogenes are mutated forms of cellular proto-oncogenes. Proto-oncogenes code for cellular proteins which regulate normal cell growth and differentiation.

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32 Class I: Growth Factors Class II: Receptors for Growth Factors and Hormones Class III: Intracellular Signal Transducers Class IV: Nuclear Transcription Factors Class V: Cell-Cycle Control Proteins Five types of proteins encoded by proto-oncogenes participate in control of cell growth:

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33 4. Nuclear Proteins: Transcription Factors 5. Cell Growth Genes 3. Cytoplasmic Signal Transduction Proteins 1. Secreted Growth Factors 2. Growth Factor Receptors Functions of Cellular Proto-Oncogenes

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34 A generic signalling pathway

Oncogenes: 

35 Oncogenes proto-oncogene = ras Oncogene = mutated ras Always activated Always stimulating proliferation

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36 amino acid position Ras gene 12 59 61 Tumor c-ras (H, K, N) Gly Ala Gln normal cells H-ras Gly Ala Leu lung carcinoma Val Ala Gln bladder carcinoma K-ras Cys Ala Gln lung carcinoma Arg Ala Gln lung carcinoma Val Ala Gln colon carcinoma N-ras Gly Ala Lys neuroblastoma Gly Ala Arg lung carcinoma Murine sarcoma virus H-ras Arg Thr Gln Harvey strain K-ras Ser Thr Gln Kirsten strain Amino acid substitutions in Ras family proteins (inactivates GTPase)

Activation mechanisms of proto-oncogenes: 

37 Activation mechanisms of proto-oncogenes proto-oncogene --> oncogene

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38 CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS Neoplasm Translocation Proto-oncogene Burkitt lymphoma t(8;14) 80% of cases c-myc 1 t(8;22) 15% of cases t(2;8) 5% of cases Chronic myelogenous t(9;22) 90-95% of cases bcr-abl 2 leukemia Acute lymphocytic t(9;22) 10-15% of cases bcr-abl 2 Leukemia 1 c-myc is translocated to the IgG locus, which results in its activated expression 2 bcr-abl fusion protein is produced, which results in a constitutively active abl kinase

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39 GENE AMPLIFICATION Oncogene Amplification Source of tumor c-myc ~20-fold leukemia and lung carcinoma N-myc 5-1,000-fold neuroblastoma retinoblastoma L-myc 10-20-fold small-cell lung cancer c-abl ~5-fold chronic myoloid leukemia c-myb 5-10-fold acute myeloid leukemia colon carcinoma c-erbB ~30-fold epidermoid carcinoma K-ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinoma

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40 Oncogenes are usually dominant (gain of function) cellular proto-oncogenes that have been mutated (and “activated”) cellular proto-oncogenes that have been captured by retroviruses and have been mutated in the process (and “activated”) virus-specific genes that behave like cellular proto-oncogenes that have been mutated to oncogenes (i.e., “activated”)

The result:: 

41 The result : Overproduction of growth factors Flooding of the cell with replication signals Uncontrolled stimulation in the intermediary pathways Cell growth by elevated levels of transcription factors

Tumor suppressor genes: 

42 Tumor suppressor genes Normal function - inhibit cell proliferation Absence/inactivation of inhibitor --> cancer Both gene copies must be defective

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43 KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES RB rb rb rb RB Familial RB (%30) Tumor cells Normal cells Normal cells Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation. RB LOH

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44 RB RB RB LOH RB Mutation Normal Cells Tumor cells KNUDSON TWO HIT HYPOTHESIS IN SPORADIC CASES RB RB Inactivation of a tumor suppressor gene requires two somatic mutations.

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45 TUMOR SUPPRESSOR GENES Disorders in which gene is affected Gene (locus) Function Familial Sporadic DCC (18q) cell surface unknown colorectal interactions cancer WT1 (11p) transcription Wilm’s tumor lung cancer Rb1 (13q) transcription retinoblastoma small-cell lung carcinoma p53 (17p) transcription Li-Fraumeni breast, colon, syndrome & lung cancer BRCA1(17q) transcriptional breast cancer breast/ovarian tumors BRCA2 (13q) regulator/DNA repair

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46 CELL CYCLE Daugther cell Mitosis DNA replication Control Point Gateway Growth Factors Cell cycle inhibitors CELL CYCLE S

Rb gene: 

47 Rb gene Rb protein controls cell cycle moving past G1 checkpoint Rb protein binds regulatory transcription factor E2F E2F required for synthesis of replication enzymes E2F - Rb bound = no transcription/replication Growth factor --> Ras pathway --> G1Cdk-cyclin synthesized Active G1 Cdk-cyclin kinase phosphorylates Rb Phosphorylated Rb cannot bind E2F --> S phase Disruption/deletion of Rb gene Inactivation of Rb protein --> uncontrolled cell proliferation --> cancer

p53: 

48 p53 Phosphyorylated p53 activates transcription of p21 gene p21 Cdk inhibitor (binds Cdk-cyclin complex --> inhibits kinase activity) Cell cycle arrested to allow DNA to be repaired If damage cannot be repaired --> cell death (apoptosis) Disruption/deletion of p53 gene Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --> cancer

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49 These are genes that ensure each strand of genetic information is accurately copied during cell division of the cell cycle. Mutations in DNA repair genes lead to an increase in the frequency of mutations in other genes, such as proto-oncogenes and tumor suppressor genes. i.e. Breast cancer susceptibility genes (BRCA1 and BRCA2) Hereditary non-polyposis colon cancer susceptibility genes (MSH2, MLH1, PMS1, PMS2) have DNA repair functions. Their mutation will cause tumorigenesis. DNA REPAIR GENES

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50 Van Gent et al, 2001 Molecular mechanisms of DNA double strand break repair BRCA1/2

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51 IMPORTANCE OF DNA REPAIR

Multiple mutations lead to colon cancer Genetic changes --> tumor changes: 

52 Multiple mutations lead to colon cancer Genetic changes --> tumor changes Cellular Tumor Progression

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53 Revolution in cancer treatment: ‘ Smart Bullets Period ’

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54 Hanahan & Weinberg 2000 Summary of 30 years of research (1971-2001)

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55 Bilimsel Araştırmaların Kanserle Savaşa Katkısı HERCEPTİN HERCEPTIN STI-571

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56 Translocation and Bcr-Abl fusion in CML

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57 STI-571 against Bcr-Abl

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58 Smart bullet STI-571 lockes itself to the target molecule STI-571

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59 Thousands of Targets HERCEPTIN STI-571 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

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60 MOLECULAR BIO LOGY & INFORMATICS Biyoinformatik ~ 30.000 genes ~ 300.000 protein ~3.000.000 interaction 1 human cell ~ 3.000.000.000 bp DNA