Molecular Biology of Neoplasias Flashcards
There is a strong rationale for the implications of ___ in the evolution of cancers
genetics
What is the molecular etiology of neoplasia/root of all cancers?
Genetic mutation
What is a mutation?
Alterations in nuclear DNA sequences (genes)
What happens to most mutations?
They are repaired
Which non-repaired genes will give rise to neoplasia?
Those that control cell growth, division, and differentiation
What are some types of DNA mutations?
- DNA point mutations
- Chromosomal translocation
- Gene amplification
Deletions can occur in…
- entire chromosomes
- parts of chromosomes
- specific genes
What are some examples of additions?
- Aberrant chromosome replication: trisomy and aneuploidy
- Amplifications and repeats
What causes genetic mutation?
- Environmental agents
- Mutations arising during normal cell metabolism
- Spontaneous errors in DNA replication and repair
What are some examples of environmental agents/mutagens causing genetic mutation?
- Chemical carcinogens
- Radiation
- Dietary carcinogens
- Tobacco smokes
What is an example of a mutation arising during normal cell metabolism?
Free radical-induced mutations
A genetic characteristic of all neoplasms is that it’s a result of ___ genetic damage (acquired or inherited)
non-lethal
What are the normal regulatory genes that are principal targets of genetic damage?
- Proto-oncogenes
- Oncogenes
- Tumor suppressor genes
- Genes that regulate DNA repair
Neoplasia is a ___ process
multi-step
How many mutations are required to generate cancer?
6-12
What is the one-hit hypothesis?
One mutation can spoil the whole bunch
When proto-oncogenes are mutated, what can they become?
Oncogenes
What are three examples of receptor mutations leading to neoplasia?
- ret: stuck in ON position
- erb: overexpression mutation
- Her2/neu: 2 copies of human epidermal receptor
The receptor mutation, Her2/neu is important in what cancer?
Breast cancer
What is an example of a G protein mutation leading to neoplasia?
ras mutation leaves G protein stuck in ON position
What are some examples of nuclear regulatory protein mutations leading to neoplasia?
myc, jun, fos genes when activated, turn on last set of genes which turn on cell division
Oncogenes encode proteins called…
onco-proteins (which resemble normal products of proto-oncogenes)
What are proto-oncogenes?
Cellular genes that promote normal growth and differentiation
Proto-oncogenes may become oncogenic by…
viral or other exogenous influences
Oncogenes are genes which promote…
neoplastic growth
Oncogenes are mutations of naturally occurring…
proto-oncogenes
Oncoproteins do not have…
important regulatory functions
Oncoprotein production in the transformed cell does not depend on…
growth factors or other external signals
What are the four classes of oncogenes?
- Growth factors
- Growth factor receptors
- Membrane associated signal transduction proteins
- Nuclear regulatory proteins
Sis encodes for…
Platelet Derived Growth Factor
Polypeptide growth factors normally stimulate…
proliferation of cells
Mutations of genes that encode growth factors render protein products oncogenic either by ___ or ___
overexpression or increased binding capacity
Normal receptor binding by growth factor results in…
transient activation of tyrosine kinase activity –> transient second messenger activity
How do oncogenic receptors differ from normal growth factor receptors?
They are either over-expressed or demonstrate persistent activation of enzyme activity –> continuous mitogenic signals to the cell
What is an example of continuous activation mutation of an oncogenic growth factor receptor?
ret continuous activation
What is an example of overexpression mutation of an oncogenic growth factor receptor?
erb overexpression
What class of oncogene is the Her2/neu gene leading to breast cancer?
Growth factor receptor mutation
Ras protein (G protein family) is the most well-studied…
membrane associated signal transduction protein
10-20% of all human cancers contain ___ mutations
ras
Ras mutation that contributes to neoplasia is a mutation that…
maintains ras protein in an activated state
What are nuclear regulatory proteins?
Proteins which are localized in the nucleus and which bind to DNA and activate transcription of proto-oncogenes
What are three nuclear regulatory proteins that may become oncogenes?
- myc
- jun
- fos
Tumor suppressor genes are involved in…
regulation of cell growth via inhibition
Inactivation of tumor suppressor genes that leads to neoplasia involves mutations of…
both alleles aka “two-hit” hypothesis
ie. recessive genes
Name seven common tumor suppressor genes
- RB
- P53 (guardian of genome)
- BRCA1/BRCA2
- NFx
- WTx
- DCC
- APC
Li Fraumeni syndrome is a mutation of which tumor suppressor gene?
P53
Breast carcinoma is caused by mutation of which tumor suppressor gene?
BRCA1/BRCA2
What mutation in DCC will cause colon carcinoma?
Deletion of DCC in colon carcinoma
P53 links cell damage with…
DNA repair, cell-cycle arrest, and apoptosis
P53 assists in DNA repair by causing… and inducing…
causing G1 arrest and inducing DNA repair genes
What happens with homozygous loss of p53?
DNA damage goes un-repaired
What percent of all cancers have p53 gene mutation?
75%
What type of gene is bcl-2?
Overexpression of bcl-2 is found where?
bcl-2 is an anti-apoptotic gene
Overexpression found in malignant lymphoma
What type of gene is bax?
Deletion of bax can lead to what?
bax is a pro-apoptotic gene
Deletion of bax can lead to malignancy
Programmed cell death is dictated by interaction/balance of…
anti- and pro-apoptotic gene products
What is telemorase?
What happens when somatic cells lack telemorase?
Enzyme which prevents chromosome shortening (by adding nucleotides)
Somatic cells lacking telemorase will eventually die
Do cancer cells “reactivate” telemorase?
Yes
