Exam #2: Neoplasia V Flashcards
What is APC? What are mutations in APC associated with?
- APC is a tumor suppressor gene that prevents nuclear transcription
- Mutations are associated with familial polyposis coli (adenocarcinoma of the colon)
What is BRCA 1/2? What are BRCA mutations associated with?
- BRCA 1/2 are tumor suppressor genes that regulate DNA repair
- Mutations are associated with Breast & Ovarian Cancer
What is RB? What are Rb mutations associated with?
- Rb is a tumor suppressor gene that Inhibits G1 to S phase transition
- Mutations are associated with Retinoblastoma & Osteogenic sarcoma
What is the WNT signaling pathway?
This is the signaling pathway that controls cell polarity during embryonic development & self-renewal of hematopoeitic stem cells
What are the function of APC & B-catenin in the WNT signaling pathway?
APC= a class of tumor suppressor that generally down regulates growth-promoting signals; mutations lead to “Adenomatous polyposis coli” i.e. APC gene
- In the WNT signaling pathway, APC causes destruction of B-Catenin
- WNT binding blocks APC mediated destruction of B-catenin & B-catenin translocates to the nucleus of the cell, upregulating cellular proliferation
Thus, APC mutations cause continuous WNT signaling via B-Catenin
What happens when there is a heterzygous vs. homozygous mutation in APC?
Heterozygous= no cancer
Homozygous= cancer
- Constant B-catenin translocation that eventually leads to FAP
What are the cancers associated with Rb gene mutations?
1) Retinoblastoma
2) Osteosarcoma
3) Soft tissue sarcoma
What is the two-hit hypothesis?
Both alleles of Rb locus must be inactivated i.e. mutated to cause cancer
- 1 allele= no tumor
- 2 alleles= tumor
Describe the development to retinoblastoma in familial cases.
- Inherited 1x mutation in Rb gene from parent
- In development, the alternate gene is mutated & leads to the development of retinoblastoma
Describe the development of sporadic retinoblastoma.
- Born normal
- Acquired mutation in one allele
- Acquired mutation in the second allele–>disease
**The key here is that the patient is born normal
What is the function of p53?
This is a tumor suppressor gene that specifically:
1) inhibits G1–>S phase transition
2) Repairs DNA
3) Activates BAX (anti-apoptotic)
I.e. p53 is “anti-proliferative, pro-apoptotic, and function in repair”
What cancers are p53 associated with?
Lung
Colon
Breast
Li-Fraumeni Syndrome
How does p53 mediate cell-cycle arrest?
- p53 prevents the transition from G1–>S phase, by acting via p21
- p21 inhibits cyclin/CD4
What does DNA damage from carcinogens activate?
p53 that binds DNA leading to:
1) Cell cycle arrest via p21
2) DNA repair via GADD45 upregulation
If p53 cannot induce DNA repair, what happens?
Upregulation of BAX leading to apoptosis
What are the ultimate effects of a p53 mutation?
1) Cell cannot repair damaged DNA
2) Cell cannot induce apoptosis in response to DNA damage that cannot be repaired
*****End result is malignant tumor
What is the mechanism of HPV?
- HPV E6 & E7 inhibit p53
- HPV E7 also inhibits p21
What is the VHL gene?
This is a tumor suppressor gene that is located on chromosome 3p
- Part of the Ub ligase complex
- Normally regulates a nuclear transcription via HIF-1a
What are the diseases associated with VHL gene mutations?
- Hereditary renal cell carincomas
- Pheochromocytoma
- Hemangioblastomas of the CNS
- Retinal angiomas
- Renal cysts
What is the Warburg effect?
This is distinct form of metabolism seen in cancer cells:
- High glucose uptake
- Increased conversion of glucose to lactose via glycolytic pathway
Why is the Warburg effect important?
The Warburg effect is how PET scans works:
- Patient given a glucose analog that radioflouresces
- Tumor takes up glucose & comes up positive on scan
What is the function of telomerase?
- Successive cell division leads to telomere shortening
- Telmoere shortening eventually results in apoptosis in normal cells
- Telomerase prevents the shortening of the telomeres
How is telomerase implicated in cancer?
Upregulation of telomerase ensures that cells avoid apoptosis
What are epigenetic changes?
Reversible, heritable changes in gene expression that occur without mutation
- Involved post-translational modification of histones & DNA methylation
