theories of cancer genesis 1 1- standard dogma proto-oncogenes (ras – melanoma) tumor suppressor...

Theories of cancer genesisTheories of cancer genesis

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1- Standard Dogma•Proto-oncogenes (Ras – melanoma)•Tumor suppressor genes (p53 – various cancers)

2- Modified Dogma•Mutation in a DNA repair gene leads to the accumulation of unrepaired mutations (xeroderma pigmentosum)

3- Early-Instability Theory•Master genes required for adequate cell reproduction are disabled, resulting in aneuploidy (Philadelphia chromosome)

Dr MOHAMED FAKHRY

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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 myelogenousChronic myelogenous t(9;22)t(9;22) 90-95% of cases90-95% of cases bcr-ablbcr-abl22

leukemialeukemia

Acute lymphocyticAcute lymphocytic t(9;22)t(9;22) 10-15% of cases10-15% of cases bcr-ablbcr-abl22

LeukemiaLeukemia

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

Dr MOHAMED FAKHRY

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GENE AMPLIFICATION

Oncogene Amplification Source of tumor

c-mycc-myc ~20-fold ~20-fold leukemia and lung carcinomaleukemia and lung carcinoma

N-myc 5-1,000-fold neuroblastomaretinoblastoma

c-ablc-abl ~5-fold ~5-fold chronic myoloid leukemia chronic myoloid leukemia

K-ras 4-20-fold colon carcinoma 30-60-fold adrenocortical carcinoma

Dr MOHAMED FAKHRY

Tumor suppressor genesTumor suppressor genes

Dr MOHAMED FAKHRY 20154

Normal function - inhibit cell proliferation

Tumor suppressor genes are genes that, when mutated, fail to repress cell division.

Absence/inactivation of inhibitor --> cancer

Both gene copies must be defective

Knudson’s Two-Hit HypothesisKnudson’s Two-Hit Hypothesis

When tumor suppressor genes are mutated, a predisposition to develop cancer often follows a dominant pattern of inheritance.

The mutation is usually a loss-of-function mutation in the tumor suppressor gene.

Cancer develops only if a second mutation in somatic cells knocks out the function of the wild-type allele.

KNUDSON’S TWO-HIT HYPOTHESISKNUDSON’S TWO-HIT HYPOTHESIS IN IN FAMILIAL CASESFAMILIAL 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’S TWO-HIT HYPOTHESISKNUDSON’S TWO-HIT HYPOTHESIS IN IN SPORADIC CASESSPORADIC CASES

RB RB

Inactivation of a tumor suppressor gene requires two somatic mutations.

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TUMOR SUPPRESSOR GENESDisorders 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

RbRb gene 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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Verification of the Two-Hit Hypothesis for Verification of the Two-Hit Hypothesis for RetinoblastomaRetinoblastoma

Several cases of retinoblastoma are associated with a small deletion in chromosome 13q. Mapping refined the RB locus to 13q14.2.

Positional cloning was used to isolate a candidate RB gene that encodes a protein that interact with transcription factors that regulate the cell cycle.

In retinoblastoma cells, both copies of this gene were inactivated.

In cell culture, expression of a wild-type RB allele could revert the phenotype of cancer cells.

Cellular Roles of Tumor Cellular Roles of Tumor Suppressor ProteinsSuppressor Proteins

The proteins encoded by tumor suppressor genes are involved in:

cell division, cell differentiation, programmed cell death, DNA repair.

p53p53 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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The Cellular Function of p53The Cellular Function of p53

Expression of p53 is very low in normal cells.

Expression of p53 increases in response to DNA damage due to a decrease in degradation.

p53 can inhibit cell division or induce apoptosis.

[ increase ]p-p53


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Dr MOHAMED FAKHRY

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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 GENESDNA REPAIR GENES

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IMPORTANCE OF DNA REPAIR

pBRCA1 and pBRCA2 regulate DNA pBRCA1 and pBRCA2 regulate DNA repairrepair

Mutations in the tumor suppressor genes BRCA1 and BRCA2 have been implicated in hereditary breast and ovarian cancer.

Both genes encode proteins that are localized in the nucleus and have transcriptional activation domains.

pBRCA1 and pBRCA2 may be involved in DNA repair in human cells.


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Dr MOHAMED FAKHRY

Chromosome Rearrangements: The Philadelphia Chromosome

The Philadelphia chromosome is the result of a reciprocal translocation between chromosomes 9 and 22 with breakpoints in the c-abl gene on chromosome 9 and the c-bcr gene on chromosome 22.

The fusion gene created by this rearrangement encodes a tyrosine kinase that promotes cancer in white blood cells.

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Translocation and Bcr-Abl fusion in CML

The Philadelphia Chromosome

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Smart bullet STI-571 lockes itself to the target molecule

STI-571

Chromosomal Rearrangements:Burkitt’s Chromosomal Rearrangements:Burkitt’s LymphomaLymphoma

Burkitt’s lymphoma is associated with reciprocal translocations involving chromosome 8 and a chromosome carrying an immunoglobulin gene (2, 14, or 22).

The translocations juxtapose c-myc to the genes for the immunoglobulin genes, causing overexpression of c-myc in B cells.

The c-myc gene encodes a transcription factor that activates genes for cell division.

A Reciprocal Translocation Involved in A Reciprocal Translocation Involved in Burkitt’s LymphomaBurkitt’s Lymphoma

8p21.1

Dr MOHAMED FAKHRY 27

Genetic Pathways to CancerGenetic Pathways to Cancer

Cancers develop through an accumulation of somatic (not a single) mutations in proto-oncogenes and tumor suppressor genes.

Multiple Mutations in CancerMultiple Mutations in Cancer

Most malignant tumors cannot be attributed to mutation of a single gene.

Tumor formation, growth, and metastasis depend on the accumulation of mutations in several different genes.

The genetic pathways to cancer are diverse and complex.

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

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Cellular

Tumor ProgressionTumor Progression

Hallmarks of Pathways to Hallmarks of Pathways to Malignant CancerMalignant Cancer

1. Cancer cells have self-sufficiency in the signaling processes that stimulate division and growth.

2. Cancer cells are abnormally insensitive to inhibitory signals of growth.

3. Cancer cells can escape programmed cell death (apoptosis).

4. Cancer cells have not limit of replication potential.

4. Cancer cells develop ways to grow themselves.

5. Cancer cells acquire the ability to invade other tissues and colonize them.

theories of cancer genesis 1 1- standard dogma proto-oncogenes (ras – melanoma) tumor suppressor...

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