93 -Neoplasia 2 Flashcards
Emerging hallmarks of cancers 1 2 3 4
Avoiding immune destruction
Tumour promoting inflammation
Genome instability and mutation
Deregulating cellular energetics
Pattern of mutations in cancer cells
Often a collection of small mutations over time which lead to malignancy.
Pattern of mutations in cancer cells
Often a collection of small mutations over time which lead to malignancy.
Aetiology of colon cancer 1 2 3 4
1) Normal mucosa (germline mutation may or may not be present, might acquire mutation - first hit)
2) Mucosa at risk (Methylation abnormalities, inactivation of normal alleles - second hit)
3) Protooncogene mutations, loss of additional cancer suppressor genes (adenoma)
4) Additional mutation, gross chromosomal alterations (carcinoma)
Four classes of normal regulatory genes that are principal targets of genetic damage relevant to carcinogenesis
- Growth-promoting proto-oncogenes
- Growth-inhibiting tumour suppressor genes
- Genes that regulate programmed cell death (i.e., apoptosis)
- Genes involved in DNA repair
Number of potentially-damaging DNA events per cell per day
~30,000 events. Almost all are repaired.
Types of genetic abnormalities that increase chance of tumour development
Alterations to ability to repair DNA
Difference between a mutation and a polymorphism
A mutation is any change in DNA sequence from normal.
A polymorphism is a DNA sequence variation common in the general population. No single allele is considered ‘normal’
Effect of SNP in a promotor
Changes amount of protein produced
Examples of DNA repair genes
BRCA1 and BRCA2
Types of mutations in cancer 1 2 3 4
Errors in DNA replication not repaired
Point mutations
Copy number mutations
Chromosomal rearrangements
Example of a gene that can amplify
N-MYC gene, associated with neuroblastomas.
Increases in copy number, greatly increases amount of gene expressed.
Double minutes
Small fragments of extrachromosomal DNA, associated with cancers.
Example of a gene translocation and fusion
BCR-ABL, leading to chronic myelogenous leukaemia.
ABL oncogene from chromosome 9, BCR locus on chromosome 22 swap.
Size of a tumour that can be detected on an X ray
~10^8 cells
How quickly can a tumour grow from 1g to 1kg?
~3 - 10 months, if unimpeded.
Major cell proliferation pathways in cancer
Usually through a growth factor pathway (binding tyrosine kinase receptor).
PI3K pathway (Ras-dependent or -independent)
MAPK (always Ras-dependent)
Manner in which RAS can be subverted in cancer
Made independent of upstream regulation.
PI3K pathway 1 2 3 4
1) Tyrosine kinase receptor.
2) PI3K converts PIP2 to IP3. This is suppressed by P10 (tumour suppressor)
3) PIP3 phosphorylates, activates Akt, which activates CREB in the nucleus
4) Transcription of genes for cell survival growth, proliferation
Difference in mutations required for cancer in oncogenes and tumour suppressor genes
Only need heterozygous mutation in oncogene.
Need homozygous mutations in tumour suppressors.
Ways that tumour suppressor genes can be subverted
Mutation in gene, leading to non-functional protein
Deletion of gene
Hypermethylation of gene (epigenetic modification)
miRNA
Small, non-translated RNAs.
Probably involved in regulating protein expression (both transcription and translation).
First tumour suppressor gene identified
Retinoblastoma
Prevalence of retinoblastoma
1/20,000 children
