p53 mutations/deletions are linked to many sporadic forms of cancer that are also seen in LFS patients
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What does figure 2 tell us?
though mutations vary between families, they are consistent within a family.
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What is the most common p53 mutation?
248 codon, C to T
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What two pathways can research on additional tumor suppressor genes proceed by?
Analysis of the loss of heterozygosity in tumor samples, and the identification and study of cancer-prone families.
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Why is the collection of a large sample size of tissues difficult? Three answers.
High mortality among affected individuals, lack of an unambiguous definition, rarity of syndrome.
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What are some functions of p53 and how does it work?
Binds to DNA. If damaged, it controls apoptosis, senescence & DNA repair
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What is the importance of the 3 band?
All affected individuals have this size band, demonstrating that the mutations could not have occurred through mistakes in PCR.
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What codons contain mutations in each family?
Family 1: 248
Family 2: 258
Family 3: 245
Family 4: 248
Family 5: 252
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What is a major problem with PCR and how did Malkin et. al address it?
Unintended mutations could alter data, YNZ22.1
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What is a new screening tool for LFS?
Ability to identify carriers
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What is the structure of the protein p53 and why is it important?
Tetramer. Even if one of the four proteins is the product of a mutant p53 allele, p53 no longer functions properly.
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Look at table 2. What does the ratio of mutant to total clones signify?
the hetero or homozygosity of the mutant allele. This also demonstrates that carriers and affected individuals can have the same number of mutant alleles.
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What exons generally contain sporadic p53 mutations?
Exons 5 through 8
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What is the trans-dominant loss of function effect?
When the mutant p53 protein causes the wild-type p53 protein to stop functioning properly (when heterozygous for p53 gene)
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What does being a carrier mean if you have LFS?
You have one mutate p53 allele (you are heterozygous), you have not yet developed LFS/shown tumorigenesis, but you are likely to.
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Why is it important that the p53 mutant that exerts a transdominant loss of function effect is selected against?
You can't test for large amounts of mutant p53 to diagnose or confirm a case of LFS, as many (as with with the rarer forms) will have less p53
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Figure 4. Which gene line expresses the most p53 and why?
the KHOS-24OS shows the most p53 because of its trans-dominant effect on wild type p53.
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What is the significance of mutant p53 protein's half life?
It has a much longer half life than normal p53. It is more stable and hence can act effectively against normal p53.
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What further direction would you take in p53 research? What questions could you ask to further investigate its function in cancer?
The answer to this question isn't in the paper but requires independent thought - could knock out parts of the pathway and assess the results, test for it in other familial cancers, etc.