Lecture 48 + DLA 32 Flashcards
What does a mutation in the RB lead to?
retinoblastoma and osteosarcoma
What does a mutation in the TP53 gene lead to?
Li-fraumenti syndrome
what does a mutation in the APC gene lead to?
familial adenomatous polyposis (colorectal cancer)
What does a mutation in the MSH2, MLH1, and PMS1/2 genes do?
Hereditary nonpolyposis colon cancer (HNPCC)
colorectal cancer
BRCA1/2 mutation?
familial breast or ovarian cancer
NF1 mutation?
Neurofibromatosis 1
WT1 mutation?
wilm’s tumor
how does wilms tumor occur?
it is an autosomal dominant inheritance pattern
loss of function of the WT1 gene (chromosome 11), thus incontrollable growth and differentiation
What is the two hit hypothesis for sporadic cancer?
mutations of both tumor suppressor genes must occur before cancer can develop
What is the two hit hypothesis for familial cancer?
The first mutation is inherited, thus the second mutation can occur in any cell.
What does the second mutation lead to?
loss of heterozygosity
What mechanisms can lead to the second mutation or second hit?
- loss through non-disjunction
- mitotic recombination
- gene deletion
- point mutation
What is the regulatory protein of the G1/S checkpoint?
Rb protein
what is the G1/S checkpoint pathway?
- growth factor presence leads to the creation of the cyclin/cdk complex
- cyclin/cdk phosphorylate Rb
- Rb then no longer represses E2F
- E2F then activates S-phase genes
no cyclin/cdk complex = no cell division
What does a mutation in the Rb protein do?
It does not bind to the E2F protein, thus their is an increase in s-phase genes and unregulated cell division
What does familial cancers look like on a pedigree?
seen in all generations
due to dominant traits
What is the diff between familial and sporadic retinoblastoma?
familial:
multiple tumors
bilateral
early onset
sporadic:
single tumor
unilateral
later onset
What are the three functions of the P53 protein?
- regulate the cell cycle (proliferation)
- scan the DNA for errors
- apoptosis
What does p53 increase the expression of?
increases the expression of proteins that lead to apoptosis
The normal APC pathway?
APC is a component of the WNT signaling pathway
- destruction of complex inactivated
- beta-catenin not degraded
- beta-catenin moves to the nucleus and forms with TCF-4
- activates growth promoting genes
when there is no Wnt signal beta-catenin is degraded
what happens when APC is mutated?
Beta-catenin is never degraded even in the absence of the wnt signal.
thus growth is occuring without the wnt signal
FAP vs HNPCC
FAP: APC mutation accelerated numerous polyps normal tumor progression gatekeeper
HNPCC: MSH2 / MLH1 mutation normal tumor initiation fewer polyps accelerated tumor progression (microsatellite instability) caretaker
explain BRCA1 and BRCA2
involved in DNA repair and apoptosis
allelic heterogenicity is relevant here
usually leads to breast and or ovarian cancer when mutated
what are the epigenetic chances in tumor cells?
tumor suppressor genes are methylated and deactivated
DNA methylation and histone modifications
