Lectures 1 + 2 - Carcinogenesis, Oncogenes and TSGs Flashcards
Name 4 of the hallmarks of cancer
Resisting cell death
Activating invasion and metastasis
Inducing angiogenesis
Avoiding immune destruction
Define carcinogenesis
Transformation of a “normal” cell to a cancerous cell
Define mutagenesis
Which stage of carcinogenesis does this equate to?
The process of genetic information changing in a stable manner, resulting in mutation
Initiation
Give two things that could cause mutations (broadly speaking)
Mutagens
Replication errors
How might direct carcinogens cause carcinogenesis?
Give an example of a type of direct carcinogen
Alter base sequence or cause strand breakage/cross-linking
Alkylating agents
How does adduct formation lead to single point mutation?
When a carcinogen binds to a base, this forms a DNA adduct.
Binding alters the structure of the base such that it no longer pairs with its normal base partner
For example, C pairs with A instead of G
When the DNA replicates, the A is read - therefore when the new strand forms, T is added
Therefore C has changed to T - single point mutation
Give 3 examples of promoting agents
Chemicals
Hormones
Inflammation
Explain the sequence of carcinogenesis in colorectal cancer
Vogelstein model
- Mutation occurs within epithelial cell of intestinal crypt - leads to inactivation of APC gene
- This results in increased division, leading to a population of hyperproliferative cells. Therefore the risk of a further mutation is higher
- This second hit comes in the form of a kras mutation - results in cells with a selective advantage
- 3rd hit is inactivation of p53
- Adenoma establishes
- Accumulation of further mutations results in malignant transformation - adenocarcinoma
Give some examples of the normal functions of proto-oncogenes
Growth factors
Nuclear proteins
Protein kinases
GF receptors
What are the 3 ways in which proto-oncogenes may become oncogenes?
Can you give an example of each?
- Single point mutations - kras
- Translocation - Bcr-Abl in CML
- Increased amount of protein due to increased expresion or increased stability - Her2 +ve breast cancer
What is kras?
What is its normal function?
What about when it is mutated?
Member of the Ras family of oncogenes
Usually activated when binding occurs at tyrosine-kinase receptors - in turn activates MAPK pathway which results in cell growth
When mutated, becomes constitutively active - activates MAPK pathway without growth factor binding to receptor - uncontrolled cell growth
What is the biology behind CML?
Abl gene from chromosome 9 translocates to chromosome 22 - ends up next to Bcr gene. This juxtaposition produces a “fusion” protein which has abnormal tyrosine kinase activity - constitutively active - results in increased phosphorylation of downstream proteins.
(Philadelphia chromosome)
How might you treat CML given its biological basis?
Tyrosine kinase inhibitor, e.g. Imatinib
What is the biology behind Burkitt’s lymphoma?
Another translocation - this time MYC gene on chromosome 8 translocates to chromosome 14 - ends up next to IgH gene.
IgH activates MYC - results in inappropriate expression of MYC in B cells - causes B cell lymphoma
What do tumour suppressor genes do?
Maintain genetic stability via DNA repair, cell cycle control etc…
Outline Knudson’s 2 hit hypothesis
Deactivation of TSGs requires two sequential mutations to deactivate the 2 alleles - hence 2 “hits” required.
If cancer is hereditary, germline mutation means that every somatic cell already has one mutation - only requires sporadic mutation in any one of those cells to provide 2nd hit and hence deactivate TSG completely.
If cancer is sporadic, must have 2 random mutations in the same cell to deactivate the TSG - far less likely.
How might TSGs be deactivated?
Loss of 1st allele usually via deletion - “loss of heterozygosity”
Other allele then deactivated via deletion, mutation or methylation
Give 2 examples of TSGs
p53
Retinoblastoma protein
What is the function of p53?
Hence what happens if it is deactivated?
Normally causes cell cycle arrest in G1 in response to DNA damage - allows time for repair
If repair successful, cycle continues, if not, p53 induces apoptosis
Hence if inactive, cell cycle progresses even if DNA damaged
What is the function of the retinoblastoma protein?
- Responsible for the major G1 checkpoint - prevents cell entering S phase until it is ready
- Usually binds to an hence inhibits E2F transcription factors
- Once cell ready to progress, Rb protein is phosphorylated by CDK-C complexes - becomes inactive, therefore releases E2F - allows cell to enter S phase
If deactivated by mutations, Rb cannot bind E2F - constitutively active - cell will progress even if it’s not ready
What are the roles of p15 and p16 regarding the Rb protein?
Both TSGs
Inhibit CDKs - therefore prevents deactivation of Rb protein - remains bound to E2F, inhibiting it
Hence if p15/p16 deactivated, Rb more likely to be phosphorylated, allowing E2F action
