Li-Fraumini Vignette

Question 1

Li-Fraumeni is?

Answer 1

Inherited cancer susceptibility syndrome, large range of presentation, autosomal dominant.
Mutation in p53. More than 50% of solid tumors have p53 mutation…
Diagnosis is important so you can catch future tumors and avoid radiation

Question 2

Criteria for Li-Fraumeni

Answer 2

Proband with sarcoma diagnosed before 45years AND first -degree relative with any cancer under 45 years AND first or second degree relative with any cancer under 45 years or sarcoma at any age

Question 3

Li-Fraumini like syndrome

Answer 3

Proband with cancer before 45, first or SECOND degree relative with typical LFS cancer AND first or second degree relative with any cancer under age 60

Question 4

LFS cancers?

Answer 4

sarcoma, breast cancer, brain tumor, adrenal cortical tumor, leukemia

Question 5

Testing for LFS?

Answer 5

direct sequence of entire p53 gene (could just do hotspots or mRNA but easy to do whole thing these days).
Next-gen.

Question 6

Knudson Two Hit Model

Answer 6

Can lose one allele (Genetic or nah) and get a 2nd hit somewhere else.. doesn’t need to be same locus/gene).

Question 7

How do you get a “hit”?

Answer 7

Point mutations (activate oncogene or inactivate suppressor)
Amplifications/deletions
Epigenetic silencing by methylation
Insertion of a retrovirus with an oncogene

Question 8

p53 fx.

Answer 8

Trx factor, big impact on cellular fx, regulates microRNAs and protein coding genes, target of conventional chemo…
fixes UV damage.
May also be used in apoptosis.

P53 is very sensitive to environmental stress, either get cell cycle arrest or apoptosis.

Question 9

p53 domains

Answer 9

Transactivation domain, DNA binding domain.