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What is the tumor progression pathway?



what is the evidence of monoclonality?

1. examination of X-inactivation pattern in cancers

2. chromosomal abnormalities of cancers

3. multiple myeloma produce a monoclonal immunoglobulin

give evidence that cancers start from a single cell


How do mutations take place?

1. environmental factors ( exogenous and endogenous)

2. germline inheritance

3. spontaneous mutations


what gene mutations could lead to cancer development?

1. proto-oncogenes

2. DNA repair genes

3. apoptosis regulation genes

4. tumor suppressor genes


what does a mutation in proto-oncogenes lead cause?

1. increase in one or more normal functions
2. new function is created

only a single allele is needed to be mutated


What do mutations in tumor suppressor genes lead to?

result in a loss of function

both alleles must be impacted


what do mutations in apoptosis regulation genes lead to?

gain or loss of function of the gene

either increase or decrease apoptosis


What do mutations in DNA repair genes lead to?

impair the cell's ability to recognize and repair nonlethal genetic damage


describe the MAP kinase pathway?

major cellular proliferative pathway

1. growth factor presence outside the cell
2. binding of the growth factor to the receptor
3. receptor autophosphorylation
4. exchange of GTP to GDP on RAS
5. RAS binds to RAF and cascade begins
6. up or down regulation of cell survival and proliferation


mutations of what 5 components of the MAP kinase pathway result in oncogene formation?

1. growth factors
2. receptors binding GF
3. tyrosine kinases
4. proteins with GTPase activity that are signal transducers
5. transcription factors


How is a growth factor receptor mutation involved with breast cancer development?

ERBB2 gene is amplified in approximately 30% of breast carcinomas leading to overexpression of the HER2 receptor and that in turn will lead to a constitutively active tyrosine kinase.


what are the two ways oncogenes are activated by gene amplification?

1. double minutes- extrachromosomal fragments
2. homogeneously staining regions- amplified oncogenes attached to the chromosome


What is herceptin (trastuzumab)?

a monocolonal antibody against the HER2 receptor, thus blocking activity

this drug will lead to the regression of the cancer


How can double minutes and homogeneously staining regions detected?

karyotyping or by FISH


What is ERBB1 and what happens if it is mutated?

a gene that encodes for the epidermal growth factors

point mutations in ERBB1 results in a constitutive activation of the EGFR tyrosine kinase

this mutation can be seen in lung cancer


Imatinib mesylate (Gleevec) does what?

a BCR-ABL tyrosine kinase inhibitor that is highly effective in CML as it suppresses the tumor proliferation