Lecture 10- Genomic instability Flashcards
Inherited loss of what causes cancer??
DNA damage response/repair proteins causes cancer
Cancer cells aquire…
a “mutator “ phenotype during progression from normality to neoplasia
What characterises a mutator phenotype ?
characterised by gross chromsomal instability and increased mutation
Checkpoints are extrinsic control pathways that:
i) ensure dependency events within the cell cycle
ii) ensure viability (if possible) when cells experience genomic stress
How were checkpoint genes identified ?
Checkpoint genes were largely identified by synthetic lethality screens in yeast
(homologues found in higher organisms)
How was the existence of checkpoint genes demonstrated ??
Existence of checkpoint pathways in metazoan cells demonstrated
by the existence of small molecules that uncouple later cell cycle stages
from earlier ones
Why are checkpoints a good target point for treatment ?
Because many cancers have acquired mutator phenotype by losing some checkpoint
gene function, we can judiciously target checkpoints to selectively kill cancer cells
What is genomic instability ??
An elevated rate of genetic alterations ??
series events that occur as a result of genomic instability..,
Normal epithelium
> Hyperplastic epithelium > early > intermediate adenomas > late
> Carcinoma > invasion and metastasis
APC
critically involved in beta catenin signalling
Wood, et al.
20,857 transcripts were sequenced for 18,191 genes
11 colon cancers were analyzed vs. normal tissue
Mutated genes were analyzed in up to 120 additional tumours to aid bioinformatic analysis
~80 mutations/cancer cell
<15 “drivers”
Analysis of gene transcripts
colon cancer
Freq of transcripts and no of mutations- common set of 15 genes < likely to be the driver mutations
Lung mutations mapped
- Point mutation in lung tumour 1000s
- Arrows indicate translocation have occurred
Does cancer occur along a set pathway ?
Many alternative routes to neoplasia
Multiple ways to go from normal to invasive carcinoma
Every tissue niche has a different profile of genes and orders required for cancer
What is important about mutations within cancer?
Mutation doesn’t necessarily mean cancer – order in which mutations occur is important
What is the mutator hypothesis?
Tumour cells acquire a mutator gene that increases the rate of mutation as an early event in development.
In tumour cells this instability takes two forms…
CIN-chromosomal instability- gross chromosomal change
MIN-microsatellite instability- concept of point mutations – base in specific seq may change
Microsatellite identified in the genome as long segments of repeated bases
- Read out of point mutations
CIN
- chromosomal aberrations-rearrangements
- loss of heterozygosity (LOH)
- aneuploidy/polyploidy
- gene amplification
MIN
• Microsatellite instability
•point mutation-base substitution,
microdeletions or insertions
CIN/MIN events
Usually very rare bu tHowever the rate of
such mutations in tumour cells may be several thousand
times higher.
Where do mutations come from and how do cells normal defend themselves ??
-DNA replication or processing errors
> Precursor control proof-reading mismatch repair
- DNA damage from exogenous agents
> nucelotide excision repair
> Base excision and double strand break repair
- DNA damage from endogenous agents - Hydrolysis, oxidation, methylation
> Base excision repair direct reversal
inherited forms of disease
- ability of cells to repair double stranded breaks is essential and significantly affect the stability – leads to genome instability
- same for Homologous recombination- involved in genomic instability
Large tomatoes
Induce repeat of S phase
Meiosis
No M phase
