17: The molecular basis of cancer Flashcards
Why does cancer become more prevalent as population ages?
live longer = more exposure to mutagens (smoke, sun, virus, radiation) = more mutations accumulated = higher chance to acquire cancer
What are cancer risk factors?
smoking, drinking, obesity
What is the molecular basis of cancer?
genetic mutations in DNA that cause biochemical defects
What are the types of mutations?
somatic/autosomal: mutation from birth
acquired: smoking, risk factor exposure, random mutagenesis, DNA damaging agents
How do we know that cancer is a genetic disease?
Susceptibility to cancer can be inherited
(This doesn’t mean an individual will get cancer, but may increase chances)
Why is DNA damage so significant?
RNA and protein can be replaced, but DNA must be preserved
Why is the cancer acquirement selected against for juvenile cancer?
no selective pressure against elderly getting more mutations bc they are past the reproducing age
Why do we have DNA polymerase that makes mistakes?
variability is required for evolution
What is the error rate in DNA replication? Why is is actually lower?
~1 in 10,000 bases synthesized
actually lower bc DNA poly proofreads and fixes some AND error could be in non-coding regions (part of protein that will not limit function)
What is the most common mutagen?
cigarette smoke: 69 chemicals known to cause cancer
avoidable causes of cancer?
other causes of cancer?
- DNA damaging agents (radiation, UV, x-rays, chemical mutagens)
- ## viruses (vaccines)
- genetics
- replication errors
is a single mutation is sufficient to cause cancer? why?
usually no
Tumour progression involves successive rounds of mutation and selection (evolution) and each round of replication acquires another mutation allowing it to grow faster or in abnormal places (selection for where most successful at dividing)
also
eukaryotes have many checkpoints to stop for repair, cell cycle control, apoptosis genes
What are the 4 characteristics pf cancer cells?
- Divide in the absence of growth factor signals
- Are immortal = Do not respond to signals that normally trigger cell death
- Have lost cell cycle control/can’t stop replication and cells don’t stop at normal cell cycle checkpoints
- Cancer cells are genetically unstable
- Cancer cells multiply in abnormal places (metastasize)
why are cancer cenlls genetically unstable?
- prone to point mutations bc they are not selected against (cancer cells don’t cause point mutations)
- cells can grow where they normally wouldn’t be able to grow
- these abnormalities are kept by cells bc they don’t follow checkpoints
What are the two main categories of cancer causing genes?
- oncogenes
- tumour suppressor genes
What are ONCOGENES?
A mutant form of a normal gene whose presence causes cancer
this is a gain of function; cells do something/are active incorrectly
How do oncogenes form?
normal cell containing normal gene (proto-oncogene) –> single mutation event –> oncogene created
What types of genetic change can result in an oncogene?
- Mutation in protein encoding region amounts
- Gene Amplification
- Chromosomal Rearrangement
What does a Mutation in protein encoding region cause?
no change in amount of protein made, protein is in hyperactive form made in normal
type of genetic change causing oncogene
What does gene amplification cause?
no oncogene, more copies of same gene in genome, normal protein overproduced
type of genetic change causing oncogene
What does chromosomal rearrangement cause?
- gene moved to different promoter region causing gene amplification: high expression of normal gene
- gene transcribed as a fusion with another protein causing hyperactive fusion protein
type of genetic change causing oncogene
What are Tumour suppressors?
A gene whose absence causes cancer. (recessive, loss of function)
How do Tumour suppressor genes form?
normal cell –> mutation event inactivates tumor suppressor gene –> no effect of mutation in one gene copy –> second mutation event inactivates second gene copy –> two inactivating mutations
What is the target of cancer causing gene?
Most oncogenes and tumour suppressors code for proteins that act in or regulate cell division or cellular differentiation
How do cancer causing genes target growth factors and cellular receptors for growth?
normal:
growth factor binds to cellular growth receptors so that the latter is activated (conformation change) and causes cell division
mutated cellular grwoth receptor:
unbound cellular receptor is always on due to conformation change that sugnals activation = cell continously divides
How do cancer causing genes target molecules involved in cell-cell interactions?
- Cell-cell interactions regulate normal growth and signal differentiation
- If these are lost cells continue to divide when they should not.
How do cancer causing genes target regulators of apoptosis?
Cancer cells do not respond to the normal signals that trigger cell death due to tumour suppressor (p53) mutation
p53 senses stressors, stops cell at checkpoint and signals for apoptosis or fixing
How do cancer causing genes target regulators of Transcription factors ?
Cancer can be caused by too much or too little expression of the genes that regulate cell growth, differentiation or cell death
can be tumour suppressors or oncogenes at the same time
How do cancer causing genes target regulators of DNA repair proteins?
Cells accumulate more and more DNA damage and thus mutations to key genes
What is Xeroderma pigmentosum (XPC)? What is the mechanism and cause?
DNA Repair Deficiencies causing skin cancer:
Melanomas develop from exposure of the skin to the UV rays of the sun which cause pyrimidine dimers in DNA that can’t be fixed
What is the cause of breast cancer?
tumour suppressors BRCA1/2 mutation inherited;
BRCA 1 mutation = ds breaks repair deficiency - NHEJ (if both are mutated this is worse)
What are the classic cancer treatment options?
- surgery
- radiation
- chemotherapy
What is the surgery/radiation mechanism for treating cancer?
- Stops cells from replicating by severely damaging DNA
- location specific
- difficult to gt all of cells, so the remaining proliferate
- radiation is targeted and doesn’t damage other tissues
What is the chemotherapy mechanism for treating cancer?
Stop cells from replicating by damaging DNA or interfering with the mitotic machinery or reducing replication substrates so cancer cells die from not having enough DNA/too much DNA damage to be viable
target cells that divide fast so that other cells can repair themselves but cancer cells can’t
exposes entire body
What is the breast cancer treatment mechanism?
- BRCA 1 mutant = no ds repair
- PARP 1 mutant = no ss repair
- give PARP 1 inhibitor to BRCA 1 mutated cell bc this causes cell death
Why is cancer treatment difficult?
-
Cancer cells develop resistance to the drug
– Cells overexpress transporters that pump out the drugs (efflux)
2. Tumours are Heterogeneous
– The cancerous cells are always “evolving” (they change with time), so in one mass of cancerous cells, some are drug reisitant, some are more mutated
3. Specificity of the treatment
– Radiation and classic chemotherapy treatments also affect normal cells (x-rays, parp 1 inhibitor effects cells without BRCA 1 mutations)
4. Different cancers have different underlying causes
5. adding antibiotics selects for more resistance
What are the goals of modern cancer treatment?
- Earlier detection
*Greater drug specificity - Combination therapies
- Identifying drugs for the “undruggable” targets
- Profiling cancer cell genomes
- Prevention
