1 molecular basis of cancer assoc.prof. işık g. yuluğ bilkent university department of molecular...
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MOLECULAR BASIS OF CANCER
Assoc.Prof. Işık G. YuluğBilkent University
Department of Molecular Biology and Genetics
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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 from1) uncontrolled cell growth or2) loss of a cell's ability to undergo apoptosis
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Cancer Cell Do Not Grow Faster ThanCancer Cell Do Not Grow Faster Than
Normal CellsNormal Cells
Rather, Their Growth is Just Rather, Their Growth is Just
UncontrolledUncontrolled
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1 fertilized egg50x101
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ProliferationDifferentiationDeath
1016 cell divisions/lifetime
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ProliferationDifferentiationDeath
Transit
Proliferating
Exiting
Renewing
Cellular equilibrium
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6ProliferationDifferentiationDeath
Cancer: disruption of
cellular equilibrium
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Post mitotic
Stem cellDifferentiatedNormal
senescent differentiated cellBenign tumorGrade 2 malignancyGrade 3 or 4 malignancy
Stem cells as the target of carcinogens
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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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• Benign tumors generally do not spread by invasion or metastasis
• Malignant tumors are capable of spreading by invasion and metastasis
Malignant versus Benign Tumors
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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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Hanahan and Weinberg, Cell 100: 57, 2000
Apoptosis
Oncogenes
Tumor Suppressor
Inv. and MetsAngiogenesis
Cell cycle
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• What is the molecular basis of cancer?
• Cancer is a genetic 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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• Theories of cancer genesisStandard 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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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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CANCER: GENOME DISEASE
• Loss of DNA• Gain of DNA• Changes in nucleotides• Epigenetic effects
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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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Chromosomal changes in the genome of cancer cells: tip of the iceberg
TerminalDeletion
http://www.tokyo-med.ac.jp/genet/cai-e.htm
RingChromosome
RobertsonianTranslocation
Deletion Reciprocaltranslocation
IsochromosomesInsertion Inversion
Duplication
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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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DNA Loss in cancer cells
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Early Brain Tumor(Astrocytoma Stage II)
Advance Brain TumorGlioblastoma Multiform (Stage IV)
DNA Loss in cancer cells: beyond coincidence ...
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p53locus
Chromosomal loss:
Mostly, it is a sign for the loss of a tumor suppressor gene
PTENlocus
CDKN2locus
RB1locus
???locus
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Cancer: Genome Disease
Epigenetic effects
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Genetic and Epigenetic Silencing of Tumor Suppressor Genes
Plass - 2002
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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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Hasar
Etken Türü
Hasar
EtkeniKanser Riski İşareti
FizikselMorötesi Işınlar Deri Ka., Melanoma P53 (CC-TT)
Radyasyon Tiroid Ka., Lösemi 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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Genes Disease Function Inheretance Cancer Risk
FA Genes F-A DNA Damage respose ? OR Lösemi
XP GenesX-P
NER Type
DNA RepairOR Skin Ca.
BLM Bloom DNA Helicase ? OR Various cancers
WRN Werner DNA Helicase ? OR Sarcoma
RECQ4Rothmund-Thomson
DNA Helicase OR Sarcoma
MLH1, MSH2,
PMS1, PMS2
MMR
DNA Repair
OD Colon, Endometrium Ca.
OR Lösemi, NF1
BRCA1, BRCA2 DNA RepairOD Breast, Ovary,
Prostate, Pancreas Ca
ATMA-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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• Approximately 90-95% of all cancers are sporadic.
• 5-10% are inherited.
CANCER AND GENETICS
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• Oncogenes
• Tumor suppressor genes
• DNA repair genes
GENES PLAYING ROLE IN CANCER DEVELOPMENT
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What are the genes responsible for tumorigeniccell growth?
Normal
Cancer
Proto-oncogenes Cell growthand
proliferationTumor suppressor genes
+
-
Mutated or “activated”oncogenes Malignant
transformationLoss or mutation of
Tumor suppressor genes
++
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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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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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4. NuclearProteins:
TranscriptionFactors
5. Cell GrowthGenes
3. CytoplasmicSignal Transduction
Proteins
1. Secreted Growth Factors
2. Growth Factor Receptors
Functions of Cellular Proto-Oncogenes
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A generic signalling pathway
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Oncogenes
proto-oncogene = rasOncogene = mutated ras
Always activatedAlways stimulatingproliferation
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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 carcinomaVal Ala Gln bladder carcinoma
K-ras Cys Ala Gln lung carcinomaArg Ala Gln lung carcinomaVal Ala Gln colon carcinoma
N-ras Gly Ala Lys neuroblastomaGly Ala Arg lung carcinoma
Murine sarcoma virus
H-ras Arg Thr Gln Harvey strainK-ras Ser Thr Gln Kirsten strain
Amino acid substitutions in Ras family proteins (inactivates GTPase)
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Activation mechanisms of proto-oncogenes
proto-oncogene --> oncogene
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CHROMOSOMAL REARRANGEMENTS OR TRANSLOCATIONS
Neoplasm Translocation Proto-oncogene
Burkitt lymphoma t(8;14) 80% of cases c-myc1
t(8;22) 15% of cases t(2;8) 5% of cases
Chronic myelogenous t(9;22) 90-95% of cases bcr-abl2
leukemia
Acute lymphocytic t(9;22) 10-15% of cases bcr-abl2
Leukemia
1c-myc is translocated to the IgG locus, which results in its activated expression
2bcr-abl fusion protein is produced, which results in a constitutively active abl kinase
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GENE AMPLIFICATION
Oncogene Amplification Source of tumor
c-myc ~20-fold leukemia and lung carcinoma
N-myc 5-1,000-fold neuroblastomaretinoblastoma
L-myc 10-20-fold small-cell lung cancer
c-abl ~5-fold chronic myoloid leukemia
c-myb 5-10-fold acute myeloid leukemiacolon carcinoma
c-erbB ~30-fold epidermoid carcinoma
K-ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinoma
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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”)
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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
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Tumor suppressor genes
• Normal function - inhibit cell proliferation
• Absence/inactivation of inhibitor --> cancer
• Both gene copies must be defective
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KNUDSON TWO HIT HYPOTHESIS IN FAMILIAL CASES
RB rb
rb rbRB
Familial RB (%30)
Tumor cells Normal cells
Normal cells
Inactivation of a tumor suppressor gene requires two mutations, inherited mutation and somatic mutation.
RBLOH
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RB RB
RBLOH
RBMutation
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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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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CELL CYCLE
Daugther cell
Mitosis
DNA replication
Control Point
Gateway
GrowthFactors
Cell cycle inhibitors
CELL CYCLE S
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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
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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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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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50Van Gent et al, 2001
Molecular Molecular mechanisms of mechanisms of DNA double DNA double strand break strand break repairrepair
BRCA1/2
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IMPORTANCE OF DNA REPAIR
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Multiple mutations lead to colon cancer
Genetic changes --> tumor changes
Cellular
Tumor Progression
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Revolution in cancer treatment: ‘Smart Bullets Period’
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Hanahan & Weinberg 2000
Summary of 30 years of research (1971-2001)
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Bilimsel Araştırmaların Kanserle Savaşa KatkısıHERCEPTİN
HERCEPTIN
STI-571
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Translocation and Bcr-Abl fusion in CML
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STI-571 against Bcr-Abl
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Smart bullet STI-571 lockes itself to the target molecule
STI-571
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Thousands of Targets
HERCEPTIN
STI-571
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MOLECULAR BIOLOGY & INFORMATICS
Biyoinformatik
~30.000 genes~300.000 protein
~3.000.000 interaction1 human cell
~3.000.000.000 bpDNA