Neoplasia 4 Molecular
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Transcript of Neoplasia 4 Molecular
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NEOPLASIA:
molecular basis of cancer
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CANCER AND GENETICS
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CANCER: GENOME DISEASE
Changes in chromosomenumbers
- Aneuploidy
Loss of DNA
Gain of DNA
Changes in nucleotides
Epigenetic effects
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Chromosomal changes in the genome of cancer
cells: tip of the iceberg
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MOLECULAR BASIS OF CANCER
Non lethal genetic damage
Clonal expansion of a single precursor cell thathas incurred the genetic damage
Principal targets of genetic damage 4 classesof normal regulatory genes : Protooncogenes
Tumor suppressor genes
Apoptosis regulating genes DNA repair genes
Multistep process genetic and phenotypic
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In normal tissues, the ratesof new cell growth and old
cell death are kept inbalance
In cancer, this balance isdisrupted
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Post mitoticStem cell
Differentiated Normalsenescent
differentiated
cell
Benign
tumor
Grade 2malignancy
Grade 3 or 4
malignancy
Stem cells as the target of carcinogens
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Essential alterations for malignant
transformation: Self sufficiency in growth signals-oncogenes.
Insensitivity to growth signals-TSGs.
Evasion of apoptosis.
Defects in DNA repair.
Limitless replicative potential.
Sustained angiogenesis.
Ability to invade and metastasize.
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Flow chart depicting the molecular basis of cancer
Fig 7-27
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Cyclin A/ cdk 2
Cyclin B/cdk 1
Cyclin E/cdk 2
CyclinD/ cdk 4
G1 S
G2M
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What are the genes responsible for tumorigenic
cell growth?
Normal
Cancer
Proto-oncogenes Cell growth
and
proliferationTumor suppressor genes
+
-
Mutated or activated
oncogenes MalignanttransformationLoss or mutation of
Tumor suppressor genes
++
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ONCOGENES
Oncogenes : Genes that promote
autonomous cell growth in cancer cells mutated forms of cellular protooncogenes.
Protooncogenes code for cellular proteinswhich regulate normal cell growth and
differentiation.
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Class I: Growth Factors
Class II: Receptors for Growth Factors
Class III: Intracellular Signal Transducers
Class IV: Nuclear regulatory proteins
Class V: Cell-Cycle regulators
Five types of proteins encoded by proto-
oncogenes participate in control of cell growth:
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4. Nuclear
Proteins:
Transcription
Factors
5. Cell Growth
Genes
3. CytoplasmicSignal Transduction
Proteins
1. Secreted Growth Factors
2. Growth Factor Receptors
Functions of Cellular Proto-Oncogenes
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Role of proto oncogenes and oncoproteins
Protooncogenes function in regulating growth andproliferation of the cell.
Oncoproteins :Similar function, but endow the cell with self-sufficiency in growth
Devoid of regulatory elements
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Oncogenes
Proto-oncogene = ras
Oncogene = mutated ras
Always activated
Always stimulating proliferation
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TUMOR SUPPRESSOR GENES
The products ofthese genes regulate/ suppress furthercell proliferation
Involved in cell cyclecontrol, regulation ofapoptosis
If abnormal :INSENSITIVITY TO
GROWTH INHIBITORYSIGNALS
Daughter cell
Mitosis
DNA replication
Control Point
Gateway
GrowthFactors
Cell cycleinhibitors
CELL CYCLE
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RB Gene
Product of RB gene is a nuclear
phosphoprotein that plays a key role in
regulating the cell cycle
In quiescent cell : ACTIVE,
HYPOPHOSPHORYLATED STATE
G1/S : INACTIVE HYPERPHOSPHORYLATED
STATE
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p53
Located on chromosome 17p13.1
Most common target for genetic alterations in
human tumorsLi Fraumeni syndrome :
Inherit 1 mutant p53 allelle
Younger age, multiple primary tumors Ca breast, adrenal cortex, sarcomas, brain
tumors and leukemias.
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MOLECULAR POLICEMAN
Prevents propagation of genetically damaged cells It acts in the cell cycle only when DNA is damaged
DNA damage :
Rapid increase in p53, protein kinases & ATM(which phosphorylate p53): Apoptosis
Important in therapy
Tumors with normal p53 respond well to chemo
and radiotherapy
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Other tumour suppressor genes
APC/b- catenin
NF-1, NF-2 genes
VHL
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DNA REPAIR DEFECTS AND GENOMIC
INSTABILITY
Hereditary Nonpolyposis Cancer syndrome
Xeroderma pigmentosum
Inherited loss ofnucleotide excision repair( NER)
Ataxia telangiectasia, Bloom Syndrome
BRCA-1 & BRCA-2 Genes
Mutations Breast & Ovary Ca
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IMPORTANCEOFDNAREPAIR
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Multiple mutations lead to colon cancer
Genetic changes --> tumor changes
Cellular
Tumor Progression
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Development of sustained angiogenesis