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Flashcards in Lecture 65 Deck (37)

What are four available paths that cause loss of heterozygosity (LOH) in retinoblastoma?

1) rb/+ --> rb/rb
2) Loss of chromosome with normal RB1 by mitotic non-disjunction (sometimes followed by duplication of remaining chromosome)
3) Mitotic crossing over proximal to RB1 locus
4) Deletion of normal RB1 allele
5) Point mutation in normal RB1 allele


How does the retinoblastoma protein regulate its cell cycle?

1) When RB1 is hypophosphorylated (In the G phases), it binds & inactivates transcription factor E2F
2) When RB1 is hyperphosphorylated, it releases E2F, allowing E2F to activate targets (S-phase)
3) If there is no RB1, there is no growth suppression


What is Li-Fraumeni syndrome?

1) Defective p53 protein
2) Wide variety of tumors that occur at an unusually young age (breast, brain, osteosarcoma, leukemia, etc.)
3) Inherited as an autosomal dominant predisposition to cancer
4) Mutations in TP53 (gene for checkpoint control protein p53) affect: DNA damage response & Apoptosis in response to genome instability
5) Individuals heterozygous for TP53 develop cancer at a frequency of >90-95% - point mutations in codon 245-258
6) Slightly more than 50% of all human cancers contain mutations in TP53 gene; the most frequently mutated of all known cancer genes


Normally, what is p53 bound to?

MDM2, which inactivates p53, so it is not used when it is not needed


What induces p53 to function?

1) DNA damage
2) Cell cycle abnormalities
3) Hypoxia
4) etc.


If there is low damage to a cell, what does p53 do?

1) Cell cycle arrest
2) DNA repair
3) Cell cycle restart


If there is high damage to a cell, what does p53 do?

1) Apoptosis
2) Destruction & elimination of damaged cells


Compare what occurs in cells with or without p53 when DNA damage occurs

1) DNA damage in WT cells: cells repaired before division, or killed
2) DNA damage in cells defective for p53: cells neither repaired before division, nor killed - mutation and proliferation of abnormal cells


What is neurofibromatosis?

1) Inherited as an autosomal dominant trait
2) Large numbers of benign neurofibromas
3) 3% of cases associated with malignant transformation
4) Mutation in Gatekeeper Tumor Suppressor Gene NF1 gene has homology to the catalytic domain of ras GAP (GTPase activating protein); called neurofibromin - keeps Ras in active GTP form
5) Perhaps only one copy needs to be mutated to give benign neurofibromas; but loss of second gene is required for malignancies


What is familial polyposis coli (FPC; A.K.A. Familial adenomatous polyposis coli (FAP))?

1) Colon - normal at birth; hundreds of small polyps form during first 20 years of life
2) Polyps are asymptomatic; significant risk of progression to colon cancer, approaching 100% by age 50
3) Autosomal dominant predisposition to colon cancer, highly penetrant (almost complete penetrance)
4) APC gene mutation - product controls the levels of a transcription factors Beta-catenin (and indirectly Myc)
5) Loss of APC genes is the first step in progression to cancer


How does Wnt normally stimulate cell proliferation?

1) Wnt binds to a cell membrane receptor
2) Binding signals APC to release from Beta-catenin destruction complex
3) Beta-catenin normally binds to intracellular portions of cadherins to stabilize them, but when it is released from APC, it will go to the nucleus to activate a transcription factor for cell proliferation
4) Beta catenin also prevents cells from piling on top of one another by regulating E-cadherins


What is the function of E-cadherin?

Glycoprotein that acts as glue between cells


What happens when APC is mutated?

1) When APC is mutated, the Beta-catenin destruction complex is no longer functional
2) Beta-catenin will continue to stimulate cell proliferation


Describe the progression of colon cancer

1) 2 APC mutations causes a nest of epithelial cells to grow on the basement membrane of the colon - this results in dysplasia (early)
2) 2 APC + 1 Kras + 2 SMAD mutations results in a break in the epithelium and an outward growth of a blood vessel with a nest of cells previously grown. This is called a polyp (intermediate)
3) More polyps begin to grow (late adenoma)
4) 2 APC + 1 Kras + 2 SMAD + 2 p53 mutations - Once polyps begin to spread their cells into the blood stream, the cancer becomes metastatic (carcinoma)


What is lynch syndrome (Hereditary nonpolyposis colon cancer (HNPCC))?

1) Colon cancer with fewer polyps, young age of onset; also other cancers
2) Autosomal dominant predisposition to cancer
3) Cells show microsatellite instability in tissue culture
4) Genes involved in repair of DNA sequence mismatches: hMSH2, hMLH1
5) Patients are susceptible to spontaneous mutations which contribute to multistep progression of cancer (Bulge mismatches can be created by misinsertion or strand slippage)


Describe characteristics of breast cancer

1) Lifetime risk to women in industrialized nations is 1 in 9
2) 90% of cases are sporadic; 10% are familial
3) Familial:
a) inheritance of one defective allele predisposes to breast or ovarian cancer
b) In half of the familial cases, mutations in BRCA1 or BRCA2 are involved
c) Both proteins are expressed in many tissues and are most abundant in S phase of the cell cycle; involved in homologous recombination
4) Sporadic: BRCA1 or BRCA2 mutation NOT found


How can mouse models be used to show effects of breast cancer in humans?

In mouse models ("Knockout mouse") lacking BRCA1 or BRCA2, defective cell division, defective DNA repair, & chromosome instability are observed


How many alleles must be mutated to have cancer in a tumor suppressor gene vs oncogene?

TSG: Both alleles
Oncogene: One allele


Can germline transmission of mutant allele occur in TSG vs. oncogene?

TSG: Frequently seen
Oncogene: Rare


Can somatic mutation be involved in tumor formation in TSG vs. oncogene?

TSG: Yes
Oncogene: Yes


What is the function of a mutant allele in TSG vs. oncogene?

TSG: Loss of function (recessive allele)
Oncogene: Gain of function (dominant allele)


What are the effects on cell growth in TSG vs. oncogene?

TSG: Inhibits cell growth
Oncogenes: Promote cell growth


What do genome instability & hypermutagenesis arise form?

1) Inactivation of replication, repair or recombination genes leading to increased mutations in all genes, including oncogenes & tumor suppressor genes
2) Aberrant checkpoint controls can give rise to aneuploidy & chromosome instability


What is Xeroderma Pigmentosum?

1) Clinical features: Sensitivity to sunlight, sking changes, & predisposition to malignancy
2) Autosomal recessive
3) Seven genes identified (XP-A, B, C, D, E, F, G)
4) Defects in nucleotide excision repair
5) Failure to excise pyrimidine dimers from UV light exposure


What is ataxia?

Poor coordination


What is telangiectasia?

Dilated blood vessels


What is ataxia-telangiectasia?

1) Atosomal recessive: Clinical features: Progressive cerebellar denegeration, immunodeficiency, growth retardation, premature aging, chromosome instability, & acute sensitivity to ionizing radiation
2) Autosomal dominant predisposition to cancer: Lymphoid malignancies, also breast cancer
3) Defective ATM gene:
a) has homology to a signal transduction enzyme for cell cycle control & meiotic recombination in yeast & mammals
b) protein acts upstream of p53 in damage response pathway; coordinates repair response
4) In AT patients, the increase in p53 fails to occur, leading to genome instability


How is ATM gene normally activated?

1) Ionizing radiation --> ATM protein kinase --> Increased p53 protein --> G1 Arrest
2) This does not occur in AT because p53 is not functioning


What is Fanconi anemia?

1) Affects all bone marrow elements, associated with cardiac, renal, & limb malformations and high incidence of leukemias
2) Inability to remove inter-strand DNA crosslinks; ~15 genes involved
3) Cultured cells show spontaneous chromosome breaks
4) Autosomal recessive disorder for non-cancerous symptoms
5) Autosomal dominant cancer predisposition


What is Bloom Syndrome?

1) Clinical features: growth deficiency, sun-sensitivity, hypo- & hyper-skin pigmentation & multiple tumors
2) Non-cancerous symptoms: autosomal recessive
3) Cancer: Autosomal dominant predisposition
4) High frequency of chromosomal breaks & sister chromatid exchanges (tissue culture)
5) Mitotic recombination leads to loss of heterozygosity
6) Bloom gene homologous to DNA helicases (defective bloom gene (BLM) in Blood syndrome)


How can one differentiate between Fanconi vs Bloom chromosomes?

Fanconi: Chromosome breaks & gaps
Bloom: High frequency of sister chromatid exchanges


What are examples of caretaker TSGs vs mutators of them?

Caretaker TSGs: HNPCC, BRCA2, BRCA2
Mutators: XP, AT, Fanconi, Bloom


Compare genome instability, hyper-mutagenesis in caretaker TSGs & mutators

Occurs in both


Compare cancer susceptibility in caretaker TSGs & mutators

Occurs in both


Compare non-cancer clinical symptoms in caretaker TSGs & mutators

Occurs only in mutators, not in caretaker TSGs


What are two types of epigenetic changes that can induce cancer?

1) Oncogenes are normally hypermethylated. Abnormal hypo-methylation can cause oncogene expression and cancer induction
2) Tumor suppressor genes are normally activated due to hypo-methylation. Abnormal hyper-methylation can lead to TSG suppression & cancer induction


What are OncomiRs?

1) Micro RNAs (19-22nt) (miRNA) are involved in regulation of gene expression
2) Because of pervasive dysregulation of gene expression in cancer, roles for miRNA are inferred
3) "oncomiRs": Some miRNAs are vastly elevated in certain cancers, and may have mechanistic roles