Flashcards in Cancer Biology 4 Deck (28):
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?
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
Many families seem to be cancer prone, regardless of the fact no specific genes responsible have been identified. How can this be?
DNA-repair genes that have been characterised so far are strongly penetrant (ie if you have a mutant gene you will most likely develop cancer) or it could be that the alleles of DNA repair genes could yield sub-optimal function (DNA repair isn't working well)
How was it proven that tumour cells had defective repair systems compared to normal cells?
Normal cells were exposed to X-ray to cause damage and then the number of aberrations were counted. Lymphocytes from breast cancer patients had significantly more aberrations than lymphocytes from normal patients suggesting that cancer 'proneness' in some families is due to inferior/sub optimal DNA repair systems
What genes have been shown to be affected/ mutated in early stage colon cancers (and now many cancers)?
Ras mutations, loss of heterozygosity at several locations also
TSG mutations are therefore shown to be more common than oncogene mutations
DNA hypomethylation at early stage leads to heterochromatin decondensation and genome instability
In cancers, are there alternative pathways/genes that are affected in individuals or the same genes to cause tumour progression?
In some cancers, such as colon, there are alternative pathways in different individuals
In pancreatic cancer, mutations are mostly acquired in the same genes and order and these mainly occur before conversion to an invasive carcinoma
What is field cancerization?
Field cancerization (also termed field change, field change cancerization, field carcinogenesis, cancer field effect or premalignant field defect) is a biological process in which large areas of cells at a tissue surface or within an organ are affected by a carcinogenic alteration(s). These are separated by normal looking tissue (even though it might not function normally) and so it looks like many independent tumours are arising
What is intra-tumour heterogeneity?
Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. Intratumour simply describes these differences within one tumour instead of between tumours (ie independent regions of one tumour can acquire more mutations- this often happens later on in cancer)
Histologically normal cells found next to a cancer is often not genetically normal. How so?
Often at an increased risk of developing another independent cancer
Before, routine tests such as PCR detected mutations in TSGs, gene amplifications and chromosome translocations. Now genome-wide screening can detect changes in all genes. How can gene expression microarrays help to analyse the levels of gene expression in a tumour relative to normal tissue?
What are the patterns that this results in called?
cDNA is prepared from RNA isolated from normal and tumour tissue, and each sample is labelled with a dye. The samples are hybridised together to a microarray that contains oligonucelotide probes that can measure the expression of genes. The relative flourescence can give an indication about whether that gene is over or under expressed in the tumour and those that correlate with the prognosis can be identified
Patterns of expression in this test are called 'signatures'
Which gene that encodes a histone methylase shows to be mutated in 3 different ways in a renal carcinoma amalysis?
SETD2- this is a sign of convergent evolution (ie it plays an important role in tumour progression)
When are anti-receptor antibodies used? Give an example of one of these therapies.
In breast cancer when the receptor is expressed at an inappropriately high level
Herceptin is an anti-HER2 antibody that is used to treat cancers that have amplifications of the HER2 gene
Many tumours express truncated extracellular domains of the receptor in the cancer. What is used then?
Small molecular inhibitors of the tyrosine kinase domain
E.g Gleevec is a small molecule inhibitor to treat Chronic Myelogenous Leukemia
When does resistance to Gleevec arise?
When the Abl gene acquires additional mutations that interfere with drug binding- backup inhibitors have been designed