Cancer Biology 4 Flashcards
What are ‘caretaker’ genes?
Genes involved in the maintenance of genome integrity
Is the chance of getting a full-blown cancer high or low? Are many events needed or just a few?
It seems low as many events are needed, however, mutations can occur in early stages of tumour development which can lead to an increased growth rate of the cell population, thereby increasing the target of mutant cells that could then acquire additional mutations, or they could act by destabilising the genome
Mutagenic processes are occuring at a high frequency in our cells. What are most mutations caused by?
Endogeneous processes (e.g hydrolytic base deamination) or by DNA replication errors
Mutations in the DNA-repair systems mean an accelerated rate of mutations and therefore tumour progression occurs.
Which sorts of mutations in repair systems cause heriditary cancer and which cause sporadic?
Inherited germline defects in DNA-repair genes cause hereditary predisposition or syndromes
Somatic mutations and epigenetic silencing in DNA-repair genes cause sporadic
Most mutations act as TSGs- ie the inactivation of both alleles is required
What different mutations can arise from the activity of DNA polymerase?
Incorporating the wrong base, leading to mismatches in newly synthesised DNA- many of these are corrected through polymerase proofreading
Can also ‘slip’ or ‘stutter’ at microsatellite repeats
What corrects mutations made by DNA polymerase?
Mismatch repair enzymes (MMR) correct base-base mismatches and short insertions/deletions that the proofreading activity did not catch. This type of repair is very important for slippage at microsatellites
What is the overall mutation rate after proofreading and repair systems have acted?
1 in 10^9 for the nucleotides incorporated during DNA replication
What do defects in MMR lead to in terms of microsatellite stability?
Destabilises it- ie microsatellites expand and contract during rounds of DNA replication
MMR defects play a big part in human cancers
Which subunit of MMR is mutated in many human cancers?
MLH1
What does loss-of-function of both alleles in a mismatch repair gene lead to?
Global DNA instability
Loss of function of an MMR genes leads to expansions and contractions at many microsatellites throughout the genome. Tumours associated with MMR defects are termed what?
Microsatellite positive or microsatellite unstable
Why are tumours showing MMR defects referred to as ‘mutator phenotype’?
Once a tumour has one of these defects, it is much more likely to acquire mutations in other genes
Lynch syndrome 1 is a hereditary predisposition to colon cancer. Colon and endometrial cancers are characterised by MMR defects. What are the specific genes that become mutated as a result of MMR defects?
MSH2, MLH1 (through methylation and silencing and this causes early and preceded histopathological alterations), MSH6 and PMS2- germline mutations
Identified by genome-wide analysis
What was surprising about some genes affected by MMR defects?
That they further inactivated other MMR proteins, causing more MMR defects
What do BRCA1 and BRCA2 germline mutants lead to the predisposition of?
Breast and ovarian cancer