Lecture 27 Flashcards
Are all genetic changes which occur in cancer random?
No there are some non-random changes reflecting specific gene alterations
What can cause gene amplification in cancer?
Extra chromosomes in which the gene is found Multiple small (double minute) chromosomes which contain the relevant gene Multiple copies of the gene arranged in a head to tail fashion in a chromosome
How does gene amplification affect cancer with regards to EGFR?
This gene is often amplified in cancer, this protein binds EGF and TGFalpha resulting in tyrosine kinase activity which induces cell growth
How does gene activation by deletion affect EGFR in cancer?
The ligand binding domain of the protein is lost, this results in loss of ligand regulation for the tyrosine kinase activity driving uncontrollable growth
What is the role of chromosome translocation in cancer?
Many characteristic transloactions are seen in cancer which results in the misregulation of genes as they are placed in new environments
How does chromosome transloaction play a role in Mantle cell lymphomas?
A t(11;14) mutation occurs where a section of c11 which contains BCL-1 is combined with a section on c14 resulting in BCL-1 being regulated by the IgH gene
How does point mutation lead to cancer?
Some genes such as RAS reqire only a single mutation to cause disease
Where can the oncogenic mutations occur in RAS?
1 of 3 locations:
codon 12.13 or 61
What is the difference between a partially transformed cell and a fully transformed cell?
A partially transformed cell has been immortalized while a fully transformed cell has undergone further oncogenic mutations which reduce dependance on growth factors,
reduce density-dependent inhibition of proliferation causing cells to form multiple layers,
Reduced adherence to substrate,
anchorage independant proliferation,
tumour formation in mice
What is an example of genetic inactivation inducing a cancer?
Retinoblastoma which is a rare cancer of the eye in children, caused by los of a normal RB1 gene
What is the pathogenesis of retinoblastoma?
The RB1 allele is lost on both chromosomes (one of these may be due to an inherited mutation)
inherited retinoblastoma develops in a single hit pattern as only one functional RB1 gene is inherited
Sporadic retinoblastoma requires two hits as both copies of the RB1 gene must undergo a mutation
What is an example of genetic inactivation via promoter methylation causing cancer?
Some cancers will have a functional RB1 gene but as the promoter is methylated they will not express its product as cytosines in the promoter are methylated resulting in the binding of repressors
What is the normal function of proto-oncogenes?
Activate proliferation
Suppress differentiation
What is the normal function of tumour suppressor genes?
Inhibit proliferation
Promote differentiation
What is the mechanism for oncogenic change in proto-oncogenes?
Amplification
Or deregulated activity (EGFR domain deletion)
Translocation (cyclin D)
Point mutation (Ras)
What are the changes to protein functions in proto-oncogenes that typically induce cancer?
Mutation gives increased or altered activity, typically gain of function
What changes to cell behaviours are induced by proto-oncogenes in cancer?
Drives abnormal cell growth
What is the mechanism for oncogenic change in tumour suppressor genes?
Gene silencing by methylation (RB1)
What are the changes to protein functions in tumour suppressor genes that typically induce cancer?
Mutation gives less activity or loss of function
What changes to cell behaviours are induced by tumour suppressor genes in cancer?
Releases cells to an abnormal phenotype
What are the 4 stages of the cell cycle?
Mitosis, Gap1 (G1), S (DNA Synthetic Phase), G2
What occurs in mitosis?
Culmination in cytokiensis where two daughter cells are produced
What occurs in G1 phase?
Cells sense the environment for growth factors, space and substrate attachment to determine if they should enter cell division or not
If non-proliferating state is enetered then the cell remains in a G0 phase
What is the restriction point?
The point in the G1 phase where the cell decides if it will enter another round of cell division or not control of this point is lost in cancer