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Flashcards in Cancer Biology 3 Deck (20)
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Tumour suppressor genes and oncogenes are often involved in the same processes but act in an opposite way. For example, if a proto-oncogene acted to stimulate cell proliferation and inhibit apoptosis to increase cell numbers, what will tumour suppressor genes do?

They will restrain cell proliferation and promote apoptosis to decrease cell numbers


What happens in cancer cells, where tumour suppressor genes are mutated? What alleles are recessive? The mutated ones or the wild-type ones?

They no longer promote apoptosis so there is an uncontrolled division of cells
Mutated alleles in the tumour suppressor gene are recessive to the wild type so loss of both alleles is needed for development of cancer


Are mutant oncogenes recessive or dominant to the wild type?

They are dominant- only one allele needed to mutate/ be activated


Existence of tumour suppressor genes was proposed by Henry Harris. He hybridised a normal cell with a malignant cell. How could he tell that the alleles responsible for the tumourigenic phenotype were recessive to the wild-type?

Because the resulting cell was non-malignant, suggesting that the wild-type alleles in the normal cell were suppressing the malignancy


Which chromosome was lost when reversion back to malignancy occured a few generations after the hybridisation?

Chromosome 11, implying this is the chromosome which contains the tumour suppressor gene
This was further supported when the introduction of normal fibroblast chromosome 11 was inserted and the cell reverted back to non-malignancy


Alfred Knudson proposed the two-hit hypothesis for the development of retinoblastoma. Which two forms of childhood retinoblastoma are there?

Sporadic- can be cured by removal of tumour, no increased risk of cancer later on in life
Heritable- multiple family members affected, autosomal dominant, even if cured, patients have increased risk of developing cancer later on in life


Knudson considered the kinetics of appearance of the sporadic (unilateral) and heritable (bilateral) forms. Which was associated with his two hit hypothesis?

Sporadic ones are rarer because they require two events to develop in the Rb alleles
Heritable only requires one; the individual inherits a mutant allele and so only one event needs to occur to mutate the other allele and for the phenotype to show


In sporadic retinoblastoma, what mutates the first allele and what mutates the second?

Normally a point mutation inactivates the first Rb allele
Large-scale DNA changes inactivate the second


What can chromosomal nondisjunction cause in the daughter cells? What else can have similar results?

Loss-of-heterozygosity if it has two copies of the chromosome containing the mutant allele
LOH often leads to large deletions
Mitotic recombination can also result in this


What is loss-of-heterozygosity?

How can loss-of-heterozygosity (this is what happens in heritable retinoblastoma) help find TSGs?

Loss of heterozygosity (LOH) is a common genetic event in cancer development, and is known to be involved in the somatic loss of wild-type alleles in many inherited cancer syndromes. The wider involvement of LOH in cancer is assumed to relate to unmasking a somatically mutated tumour suppressor gene through loss of the wild type allele

Using genetic markers such as RFLPs and SNPs, we are able to identify where TSGs may lie in LOH situations


Neurofibromatosis is transmitted as an autosomal dominant predisposition to cancer. The progenitor to the malignant cell is thought to be the Schwann cell that wraps around the peripheral neurons. What does NF1 do in the Ras signalling pathway?

NF1 gene acts as a GTPase activating protein which acts in the process of preventing constitutive signalling in the Ras pathway- therefore the inactivation/mutation of this gene means deregulation of the Ras signalling pathway


Which three mechanisms can activate Ras signalling?

Oncogenic growth factor receptor alteration
Ras mutations
NF1 mutations (TSG inactivation)


The p53 TSG is mutated in most human cancers. When are there high levels of p53 present in a cell?

When the cell is under stress. Normally, p53 levels are kept low due to degradation of it. During stress, this ubiquitination stops


What is p53?

p53 is a transcription factor that activates genes involved in processes such as apoptosis and cell-cycle arrest


What is MDM2 and what happens to it in human cancers?

It is naturally occurring in cells and is what links p53 to degradation
In cancers, there are high levels of this to keep p53 levels low


What is ARF?

ARF binds to MDM2 to inhibit it from degrading p53 so if there are low levels of ARF then there are high levels of MDM2 activity (degrading p53)

i.e ARF is a tumour suppressor gene


Where are mutations seen in the p53 protein?

Remember p53 can also be inactivated by interaction with the protein products of some DNA tumour viruses, not just through its regulation by MDM2

in the DNA binding domain


What are sort of mutations are found in p53? What sort of effect does this lead to?

This leads to a dominant-negative effect


Tumour suppressor genes can also be inactivated by DNA methylation of their CpG islands. What is the correlation between high levels of DNA methylation and the types of tumours?

Positive correlation between methylation levels are high-grade aggressive tumours


What is methylator phenotype?

When tumours overexpress the DNA methyl-transferase DNMT3B and have extensive methylation of their genes