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
What does DNA methylation result in?
Reduction of expression of histone modification and compaction of DNA into heterchromatin
What is MicroRNA? Why are they important?
- 19-24 nucleotide family of noncoding RNAs that regulate messenger RNA function at the post-transcription and translational level
- New evidence suggests that they can be used for diagnostic, prognostic, and therapeutic purposes
What are the general categories of carcinogenic agents?
1) Chemical carcinogens
2) Radiation
3) Oncogenic viruses & microbes
What is carcinogenic in tobacco smoke?
Polycyclic hydrocarbons
What are chemical carginogens?
Highly reactive “electrophiles” that remove electrons from DNA, RNA, or proteins
What is the difference between a direct acting and indirect acting chemical carcinogen?
Direct= act without modification
Indirect= require metabolic activation
What are the steps involved in chemical carcinogenesis?
Generally, there are two phases of carcinogenesis:
1) Initiation
- electrophilic intermediate causes DNA damage
2) Promotion
- cell proliferation leads to a preneoplastic clone that then accumulates additional mutations
*****The key point here is that initiation must come before promotion & BOTH phases are required for tumorigenesis
What are the direct acting compounds involved in initiation?
Chlorambucil
Busuflan
Melphalan
What are the indirect compounds involved in initiation?
Polycyclic aromatic hydrocarbons
What is the source of polycyclic aromatic hydrocarbons?
1) Cigarette smoke
2) Smoked meats & fish
Where do aromatic amines and azo dyes cause problems?
Liver
What is B-naphthylamine? What occupations is this associated, and what cancer is it associated?
This is a metabolite of aniline dye that works in rubber & textile industries are exposed to
- Causes bladder cancer
What is Aflatoxin B1?
Fungal toxin produced by Aspergillus flavus in improperly stored corn, rice, and peanuts
What cancer is Aflatxoin B1 associated with?
Hepatocellular carcinoma due to p53 mutations
Nitrosamines & Amines
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What is asbestos exposure associated with?
Mesothelioma
Lung cancer
GI cancers
What are chromium and nickel exposure associated with?
Lung cancer
What is arsenic exposure associated with?
Skin cancer
What are the promoters of chemical carcinogenesis?
Estrogen
High dietary fat & bile acids
