Molecular hallmarks of cancer cells Flashcards
What 2 key events are needed for the transformation from normal to neoplastic cells?
1) Oncogene activation
2) Tumour suppressor gene inactivation
What are caretaker genes?
Genes which maintain genetic stability by repairing damaged DNA and replication errors, controlling the accuracy of mitosis - mutant forms of these genes cause genomic instability
What role do caretaker genes play in carcinogenesis?
Mutations in caretaker genes results in genomic instability - genetic instability is important for enabling specific genetic alterations to accumulate in carcinogenesis
Genetic instability is a common feature of most tumour cells
Why is genetic instability important a common feature of tumour cells?
Just clonal expansion is not enough to aquire the necessary mutations for neoplasm as the normal mutation frequency is not high enough so genetic instability is a key factor
What are the 2 types of tumour suppressor genes?
1) Gatekeepers
2) Caretakers
What are gatekeeper genes?
Genes which play an important role in regulating normal growth
Name 3 types of gatekeeper genes?
1) Negative regulators of the cell cycle and proliferation
2) Positive regulators of apoptosis
3) Positive regulators of cell differentiation
Carcinogens induce molecular abnormalities in tumour suppressor genes which lead to what change in function?
loss of function
What is required for TSG’s to become inactivated?
A first and a second hit - loss of heterozygosity
After the first hit, the single remaining normal copy of TSGs is capable of doing the job of 2 genes - the second hit is required for complete loss of function
The first hit in TSG inactivation is normally what kind of mutations?
A point mutation in the coding sequence of the gene
The second hit in TSG inactivation is normally one of what 3 types of mutation?
1) Chromosomal non-dysjunction
2) Epigenetic inactivation through promoter methylation
3) Mitotic recombination
What is different about TSGs in people with familial cancer syndromes?
Every cell in their body will carry the first hit mutation
Individuals with retinoblastoma carry a mutation in what gene, is this a caretaker or gatekeeper gene and what is the principle tumour?
RB1 - gatekeeper gene
Retinoblastoma is principle tumour
Individuals with Li-Fraumeni syndrome carry a mutation in what gene, is a caretaker or gatekeeper and what are the principle tumours?
p53 - gatekeeper/caretaker gene
Sarcomas and breast tumours are the principle tumours
Individuals with familial adenomatous polyposis carry a mutation in what gene, is it a caretaker or gatekeeper and what is the principle tumour?
APC - gatekeeper gene
Colorectal tumour
Individuals with familial breast cancer carry a mutation in what gene, is it a caretaker or gatekeeper gene and what is the other principle tumour?
BRCA-1, BRCA-2 - caretaker gene
(breast) and ovarian tumours
Individuals with hereditary non-polyposis colorectal cancer carry a mutation in what gene, is it a caretaker gene or gatekeeper gene and what is the other principle tumour?
hMLH1, hMSH2 - caretaker gene
(colon) and endometrial cancer
What a proto-oncogenes?
Genes which promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
What is meant by oncogenes?
Proto-oncogenes which have aquired a mutation. Mutations of proto-oncogenes lead to activated versions or increased expression of proto-oncogenes - oncogenes
Mutations in proto-oncogenes lead to what change in function?
Gain of function
What 4 things do oncogenes cause?
1) Increased levels of cell proliferation
2) Cell survival
3) Angiogenesis
4) Inhibition of apoptosis
How many copies of proto-oncogenes need to be activated in order to induce a gain of function?
Only 1 copy of the gene needs to be activated to induce a gain of function, mutated gene is dominant to the other normal parental gene