General genetic features of neoplasms Flashcards
What are three examples of treatments targeting the ‘hallmarks’ of cancer?
Replicative immortality = telomerase inhibitors - cancer cells reactivate telomerase which allows maintenance of telomeres so replication can continue indefinitely
Angiogenesis = Inhibitors of VEGF signals to prevent angiogenesis, reducing ability of metastasis
Evasion of growth suppressors = cyclin-dependent kinase inhibitors - kinases are involved in regulation of the cell cycle are are activated by cyclins to allow progression through the cell cycle. Inhibiting there action can prevent cell cycle progression
What are four classes of normal regulatory genes that are mutated in carcinogenesis?
Proto-oncogenes - promote growth
Tumour-suppressor - inhibit growth
DNA repair genes - repair damaged DNA to prevent mutations
Genes that regulate apoptosis - to prevent continued proliferation of damaged cells
What is the significance of mutations in DNA repair genes and carcinogenesis?
Often inherited and how familial cancers arise
Abberent function of these genes allow rapid accumulation of SECONDARY mutations, usually affecting pro to-oncogenes and TSGs leading to cancer development
What is a common example of inheritable mutations in DNA repair genes?
BRAC1 and BRAC2 in breast cancer
What are commonly examples of mutated proto-oncogenes, what is the general and how many alleles need to be effected?
MYC, Ras, Her2-Neu
Rapid uncontrolled growth
Requires mutation in only one allele to cause effect
What are commonly examples of mutated TSGs, what is the general and how many alleles need to be effected?
p53, PTEN, Rb, APC
Allows continued unregulated growth
Requires mutation in BOTH alleles to cause effect
What are common mutation types that occur in cancer?
Errors in DNA repair
Point mutations - activate oncogenes or inactivate TSGs
Oncogene amplification - not mutations but significant increased expression of the gene
Chromosomal rearrangements - translocations & fusion i.e. Philadelphia chromosome in CML
What is the difference between a SNP & mutation and can SNPs cause cancer?
Point mutation results in an allele which is abnormal and not common in the population
SNPs are point variations that are common variations of alleles in the population
Single SNPs don’t usually cause cancer but accumulation of many SNPs can lead to an increased risk
SNPs in non-coding regions can increase the amount of protein translated
What TSG function do p53, PTEN and Rb have?
Rb & p53 directly inhibit the cell cycle
PTEN inhibits oncogenic pathways
What is a loss of heterozygosity?
Loss of normal function of one allele of a gene when the other allele was already inactivated
When this occurs in TSG genes then uncontrolled growth can occur, leading to cancer development
What is the effect of N-MYC oncogene amplification?
Results in neuroblastoma in children
Increased expression of the gene leading to increased protein and thus more aggressive cancer
What cell growth pathway is most important in cancer growth?
How is it activated and what is an important regulator?
Tyrosine kinase receptor pathway - specifically the P13 kinase pathway
Normal cell growth requires external signals to initiate cell growth. A major pathway is through GFs that bind to tyrosine kinase receptors.
P13 kinase pathway then results increased transcription allowing cell cycle initiation
PTEN is an important inhibitor of this pathway
How do mutations in RAS genes (i.e. H-ras and K-ras) affect cell growth?
When growth factors bind receptors it leads to the activation of RAS (which is otherwise inactivated)
Activated ras leads to activation of the MAP-Kinase pathway relaxing to transcription and cell cycle progression
Mutations in raw means that they are permanently active, allowing constant cell cycle progression
What is the only known example of a single allele TSG mutation resulting in cancer? What cancer does it cause?
Inherited mutation of one Rb gene allele
Leads to retinoblastoma at early age
Good prognosis with early removal of the eye - leads to blindness
How do changes to miRNAs influence gene expression and how is this associated with carcinogenesis?
miRNAs are epigenetic regulatory mechanisms which influence the level of expression of a specific genes, via a hairpin structure.
Increased miRNA can lead to increased suppression of TSG expression and thus reduced TSG function
Decreased miRNA can lead to reduced transcriptional suppression and thus increased proto-oncogene expression
How does DNA methylation effect TSG function and carcinogenesis?
DNA methylation is an epigenetic regulatory measure - methylation of DNA around promotor regions
If there is too much methylation it will silence TSG expression and thus transcription of TSG proteins - increased risk of cancer
Excess methylation silencing TSG can be an inheritable trait
What are the extrinsic and intrinsic mechanisms of apoptosis?
How do tumour cells evade this process?
Extrinsic = FasL/Fas (CD95) mediated –> Caspase pathway –> death
Intrinsic = stress leading to DNA damage –> p53 response –> reduced BCL proteins (anti-apoptotic) and increased BAK/BAX proteins (pro-apoptotic) –> release of cytochrome c from mitochondria –> caspase pathway –> death
- Downregulation of Fas (CD95)
- Upregulation of BCL proteins (anti-apoptotic)
- Reduced BAK/BAX proteins (pro-apoptotic)
What mechanisms do tumor cells gain cell immortality?
Normally cell cycle is regulated at check points by the length of the telomere, shortening of the telomere prevents continued cell cycle - puts a limit on the number of cell cycles it can undergo. Telomeres initially added by telomerase
Reactivation of telomerase allows tumor cells to avoid check points and continue cell cycle, even with shortened telomeres
How do tumours metastasis?
Detachment of tumor cells from each other
Degradation of the ECM
Attachment to non-ECM components and migration
Abberent expression/down regulation of adhesion factors allow tumour cells to ‘escape’
i.e. Cadherins, beta-catenin and connexins
How do tumour cells create their own blood supply?
Produce vascular endothelial growth factors (VEGFs) that allow angeiogenesis
