EXAM2_L23_L24_Cancer_Biology_Genetics_of_Cancer Flashcards
What is Cancer?
- Genetic Disease (hereditary or spontaneous)
- Result from accumulation of somatic mutations clustered in one cell
- Loss of cell cycle control (g1,s,g2,m)> uncontrolled proliferation
- All cancer due to mutations passed to other cells
- Multi-factorial disease
What are the 1st and 2nd most common cause of death in the USA?
Who is at risk for cancer?
1st- Cardiovascular Disease
2nd- Cancer
OLD PEOPLE
- family history of cancer (10-20% due to inheriting alleles that predispose individual to cancer)
- Men
- individuals from developed countries due to environment
What are the 4 Classes of Tumors?
Where are each derived from?
Which one is most common?
- CARCINOMA (epithelial cells)- 90% malignant tumors
- lung, prostate, breast, skin, colon - SARCOMA (supporting- CT, BV,Fat, Muscle, Bone) 1%
- LYMPHOMA (Immune system cells) solid mass blood cells
- LEUKEMIA (blood-forming tissues-lymph & bone marrow)
- large proliferation of malignant blood cells in bloodstream
What are the 4 major causes of cancer?
- Chemical
- Viruses (HPV)
- Genetic Factors (protooncogenes->oncogenes)
- Point mutations: RAS
- Gene amplification: MYC
- Gene rearrangeent: Burkitt’s lymphoma/philadelphia
chromosome
- Tumor suppressor genes: TP53 & Rb
- Inherited mutations/alleles: (TP53,RB,DNA repair genes) - Obesity
How common is it for humans to get cancer due to exposure to carcinogens?
What are some examples?
How do carcinogens work?
80% of Cancers due to exposure to carcinogens!
- ie:
- UVB- distorts DNA structure
- X/Gamma rays- dsDNA breaks
- Chemicals that interact directly w/ DNA
Tumor Initiators vs Tumor Promoters (examples?)
What will cause cancer?
Initiators are mutagenic (damage DNA)
Promoters stimulate cell proliferation of initiated cells
-repeated exposure of promoter w/ initator will cause cancer
promoter ex: infection, alcohol, drugs, smoke inflammation
Tumor viruses how common? What seen in RNA viruses? What seen in DNA viruses? ex of DNA virus?
15% caused by viruses
-Viral (RNA/DNA) into host genome
RNA- inhibits regulation of cell cycle, apoptosis, and signaling pathways
DNA-inhibit tumor suppressor genes (TP53>p53) & RB
-HPV (DNA virus)> Cervical Cancer
HPV one-two punch
What two proteins does HPV encode?
What do each inhibit?
E6 & E7 inhibit DNA damage control mechanisms
- E6 binds P53 (p53 destroyed)- inhibits STOP of cell cycle and inhibits apoptosis
- E7 binds Rb- (Rb can’t bind/inhibit E2F to STOP at restriction point of G1)
EF2 is FREE to go into S phase and Duplicate DNA
HPV Vaccine? Generic name? What is it? What is it made of? How does it work?
Recombinant HPV Quadrivalent Vaccine: Gardasil
- Vaccine is the “coat proteins” of (HPV16,18-cervical cancer) and (HPV6,11- genital warts)
- immune system will illicit response if encounters real HPV
Genetic Mutations: what types?
Where mostly found?
what two types of genes affected by mutations?
- inherited or spontaneous
- DNA repair enzymes or signal transduction pathway proteins
1. Proto-oncogenes
2. Tumor suppressor genes
Proto-oncogenes & onchogenes
How do proto-oncogenes become oncogenes?
3 ways
proto-oncogenes = normal function
- oncogenes function when they shouldn’t
- gain of function mutations
- point mutation (altered product)
- Amplification (gene overexpression)
- Gene arrangement/translocation
Proto-oncogenes converted to oncogenes:
POINT MUTATIONS:
Point mutation converts proto-oncogene to oncogene
- RAS is stuck ON/ACTIVE (lost ability to take GTP>GDP)
- 1/3 human tumors RAS is converted to oncogene
Proto-oncogenes converted to oncogenes:
GENE AMPLIFICATION:
-DNA replication error increases # gene copies of a TF in a chromosome:
- MYC gene amplified on chromosome
- MYC mRNA transcripts increased
- MYC proteins behave as oncogenes in abnormally large amounts
- NO MUTATION-JUST TOO MUCH OF A GOOD THING
- MYC is an early response TF gene induced when cell gets signal to divide
Proto-oncogenes converted to oncogenes:
GENE ARRANGEMENT
(amplification of MYC due to rearrangement):
What happens?
What is a type of cancer resulting from MYC gene arrangement?
What happens and where?
MYC gene of chromosome is rearranged onto a more active promoter
- BURKITT’s LYMPHOMA t(8;14):
- Translocation of proto-oncogene MYC on Chromosome 8 to highly active promoter on 14.
-EXCESS MYC PROTEIN acts as oncogene
Proto-oncogenes converted to oncogenes: GENE ARRANGEMENT (Translocation of a gene):
Where is translocation? between what chromosomes?
What is the short chromosome called?
Where is it found? How common is it found there?
What is the Fusion Gene created?
What is the oncogene?
t(9;22)
translocation between chromosomes 9 & 22
chrm 22 is SHORT called “PHILADELPHIA” chrmsm
-Found in 95% of chronic Myelogenous leukemia (CML)
BCR-ABL FUSION GENE- (abl(9) fuses to bcr(22))
—FUSION PROTEIN IS ONCOGENIC
MITOGENIC PATHWAY CORRUPTION:
What three points of receptor-tyrosine kinase signaling can become overactive as a result of oncogene mutations?
What will increase in signaling of these three things ultimately increase? What will be the result?
- RTK
- RAS GTPase
- Transcription factor MYC
Increase CYCLIN D- > Allows cells to cross restriction point
RTK
Two types that are OUT OF CONTROL!
Receptor Tyrosine Kinases
Truncated RTK- continuously send growth signal w/o ligand
Amplified RTK- HYPER signal w/ small amounts of ligand
What two types of genes do mutations affect?
- Proto-oncogenes
2. Tumor suppressor Genes
Loss of Function Mutations
TSG= Tumor suppressor Gene
TWO Examples of TSG’s
Mutated TSG are DEACTIVATED
-lose normal function of STOPPING cell cycle
- TP53 (encodes p53) “guardian of the genome”
- – Key in DNA damage response
- Normal conditions (low p53)
- if DNA damage– STOP proteins and high p53 protein
- > 50% human tumors mutated/deleted tp53 gene!
What is normal and mutated function of p53
p53 normally STOPS cell cycle, DNA repair, apoptosis
Mutated- p53 inactive- NO DNA repair, apoptosis. Cant STOP cell cycle
TUMOR suppressor gene RB
Normal and mutated RB function
Normal: Rb binds E2F & STOPS g1->S cycle
(until phosphorylated by cyclinD-CDK4/6 then CyclinE-CDK2)
- E2F is activated when RB leaves and cell can go past G1-S
MUTATED:
Rb can’t bind E2F- ACTIVE E2S->DNA synthesis stuck ON
What disease is caused by inheritable mutation of RB?
Retinoblastoma
Familial-
Sporadic
What is the knudsen’s “two-hit” Hypothesis?
Spontaneous Vs inherited
Mutation of two copies of RB are required to give rise to a retinoblastoma
Spontaneous RB mutation in somatic cell then a second spontaneous mutation in a retinal cell to get retinoblastoma
Familial inheritance is first hit, (all somatic cells have one rb mutation- Autosomal dominant inheritance)- Both copies need mutation to manifest disease
90% penetrance (not all familial rb mutation affected)
Li-Fraumeni Syndrome
What defect of?
How common?
What happens if you have it?
Hereditary defect in TP53 (tumor suppressor gene)
- VERY RARE (few hundred people ever)
- 90% chance developing some type of cancer
- can develop multiple types of cancer
DNA repair defects in humans
What genes? Function? Familial Cancer?
HIGH RISK for tumor development
-Each division has greater risk for more mutations that are not accurately corrected
MSH2,MLH1 (DNA mismatch repair)-colon cancer (HNPCC)
XP GENES(Pyrimidine dimer repair)-Xeroderma Pigmentosa
BRCA1,BRCA2 (DNA break repair)- Familial Breast Cancer
HNPCC What is it called? What genes mutated? What are they involved in? What type of inherited pattern? How does it present? How common is this? What does it take to develop cancer? How fast?
Hereditary Nonpolyposis Colon Cancer (HNPCC)
“LYNCH SYNDROME”
-MSH2,MLH1 Gene Mutations (DNA repair mechanism)
-Autosomal Dominant
-presents w/
BRCA1/BRCA2 Mutations
What type of genes?
What cancer linked with them?
If BRCA1/2 mutated How common develop breast/ovarian cancer?
Tumor suppressor genes linked with Familial Breast Cancer
-Needed to repair dsDNA breaks
-40-80% w/ mutations develop breast cancer
15-40% w/ BRCA mutations develop ovarian cancer
XP What called? What damaged? What sensitive to? What type of inherited pattern? Normal damage from UV and normal repair? XP damage and repair? How likely is Xp to get skin cancer? Average age to get cancer with xp?
Xeroderma Pigmentosum (XP) Mutated DNA repair mechanism for UV radiation damage -Autosomal recessive (both parents carriers)
NORMALLY: pyrimidine dimers formed by UV (TT,CC,CT) and repaired by NER (nucleotide excision repair)
XP: No DNA repair, damage accumulates cells die or become cancerous
1000x more likely to get skin cancer
average age=8 vs normal 50yrs
NF1 What called? How common? What type of inherited pattern? What is mutated/abnormal? What goes NF1 Gene encode? How does it present? What is it characterized by (3 things)? What is penetrance of disease?
Neurofibromatosis Type 1 (NF1)
Most common inherited neurological disorders (1/3000)
-Autosomal Dominant
-Mutation and/or inactivation of both copies of NF1 Gene
-NF1 Gene encodes neurofibromin protein
-Neurofibromas (benign tumors of Schwann cells) around nerves in PNS
-Cafe’ au lait, cutaneous neurofibroms, Lisch nodule
100% penetrant (everyone will display symptoms-varying degrees)
How does neurofibromin protein normally function?
What happens when NF1 Mutated?
NF1 is a GTPase Activating Protein (GAP)
-NF1 Deactivates RAS (by stimulating RAS GTPase)
-
Mutated NF1 can’t deactivate RAS –> Cancer
FAP APC (adenomatous polyposis coli gene) How does it present? Why so serious? Average age? Treatment?
- Familial Adenomatous Polyposis (FAP)
- Colon & Rectum Cancer
- Heritable APC gene mutation (inherit 1 bad copy, then lose other copy in a colon/rectal cell)
- Develop thousands of colorectal polyps (adenomas)
- At least one progresses to carcinoma
- Average age 39
- Entire colon needs to be removed or polyps become malignant
APC protein What is it called? What classified as? Part of what pathway Normal Function of APC?
Adenomatous Polyposis Coli protein
-APC is tumor suppressor gene
- Part of WNT signaling pathway (cell proliferation during embryonic development)
- Normal function: APC part of “destruction complex” that degrades free Beta-Catenin (proto-oncogene, adherens junctions of ec’s, transcription coactivator in nucleus)
Beta-Catenin
- Proto-Oncogene
- Part of Adherens junctions in PM of EC’s (in cytoplasm)
- Transcription coactivator stimulates growth genes (in nucleus)
Destroyed by normal functioning APC protein
WNT
What is it? What does it do?
What is APC?
Signaling molecule that binds GPCR
-Inhibits APC & STOPS B-Catenin degradation
APC- “adenomatous Polyposis Coli” (TSG)- degrades Bcatenin
WNT Signaling of APC and B-Catenin:
What is normal function without signal?
Function With growth signal?
Function With mutated APC cells?
WNT- No growth signal:
- “destruction complex” DEGRADES B-Catenin
- GF gene transcription INHIBITED- NO PROLIFERATION
WNT-w/ Growth signal:
- “Destruction Complex” is DEACTIVATED
- Beta-Catenin enters nucleus & ACTIVATES Transcription of Growth associated Genes.= PROLIFERATION
WNT w/ Mutated cells:
- no signal
- APC mutation permanently INHIBITS destruction complex
- B-catenin ACTIVATES transcription gene factors
- Cell Proliferation (even w/o growth signal)
WNT Signaling Summary:
No Growth Signal:
w/ Growth Signal bound to GPRC:
Mutated APC:
WHAT SECRETES WNT GROWTH SIGNAL?
- no growth signal= degraded B-catenin- no proliferation
- growth signal bound= B-catenin in nucleus= Proliferation
- Mutated APC= No destruction complex= Proliferation
Stromal cells of colon secrete WNT growth signal
Cell migration/Polyp formation of colon :
How do colon cells replicate and have continuous turnover?
What happens with mutated APC?
- Stromal cells secrete GF: WNT (binds GPCR on colonic stem cells)
- Colon crypts replicate and differentiate as migrate upward
- WNT signal decreases as they get further away (causes division to stop but continued differentiation until sloughed off at top of crypt)
- Results in continuous turnover of cells
-APC mutation- cell proliferates w/o signal- polyps form in upper crypt.
(because proliferation becomes greater than loss/differentiation)
OBESITY & CANCER RISK
What happens to adipocytes?
What decreases risk? recommended amount?
Obese people have greater risk to get cancer
-As adipocytes increase size, make different signaling proteins and loses regulation
Physical activity decreases risk of cancer (150min/week)
7 Tumor suppressor genes mutated in human cancers What genes? What pathway affected? What familial cancer syndrome? Inheritance pattern?
- RB (restriction point G1 control)-Retinoblastoma
- TP53 (DNA damage/apoptosis)-Li-Fraumeni
- APC (prevents B-Catenin Growth signal)-FAP
- NF1 (inhibits RAS signal)-Neurofibromatosis type 1
- BRCA1,2 (DNA break repair)-Familial breast cancer
- MSH2,MLH1 (DNA mismatch repair) HNPCC LYNCH
- XP Genes (pyrimidine Dimer repair) Xeroderma pigmentosa (RECESSIVE)- all others are DOMINANT
Gain of function mutations:
What kind of genes?
What mutation required?
Examples?
Loss of function Mutations:
What kind of genes?
What mutation required?
Examples?
Gain of Function Mutations
-Oncogenes
-Only needs one copy of mutated gene to promote cancer
IE: RAS, MYC (Overactivation->Proliferation)
Loss of Function Mutations:
-Tumor Suppressor Genes:
-Require two inactivating mutations to promote cancer
IE: RB,TP53,APC,NF1,BRCA1,2,MSH2,MLH1,XP
(Loses ability to suppress tumor growth» Proliferation)
Targeted Therapy Treatments:
3 anticancer strategies?
- Immunotherapy- (antibodies against tumor cells)
- Inhibition of cancer-promoting proteins
- Inhibition of Angiogenesis (Prevent BV growth for tumor)
Immunotherapy: HERCEPTIN What does it target? What is HER2? How does HER2 become oncogenic? how common HER2 overexpression in breast cancer? How does HERCEPTIN work?
Targets HER2 (human epidermal growth factor Receptor 2)
HER2-
-RTK family, Oncogene via gene amplification
= too many receptors->overproliferation
-25% of breast cancer cells overexpress HER2 Gene
- HERCEPTIN (antibody against HER2 receptor)
- blocks receptors on breast cells and cell growth
Immunotherapy: RITUXAN
What does it bind?
What does it inhibit and induce?
What does it treat? when approved?
Binds cell surface protein present on Malignant B lymphocytes (in 95% of the disease)
- Binds antibody to receptor inhibits growth and induces apoptosis
- Approved in 1997 for non-hodgkin’s B-cell Lymphoma
Targeted Therapy:
Inhibiting activity of cancer-promoting proteins
What RTK inhibitor drug used for cancer?
What cancer does it treat? CML
How does CML work and how does this drug treat it?
Block proteins required for tumor growth
-Imatinib (Gleevec)- RTK Inhibitors for cancer
IE: Philadelphia chromosome CML (Chronic Myelogenous Leukemia), t(9;22)
- BCR-ABL on 22 creates FUSION PROTEIN that continuously activates RTK.
Blocks fusion protein from continuously activating RTK
- (Gleevec binds ABL tyrosine kinase and prevents phosphorylation of substrate proteins–>blocks signal for cell proliferation)
Targeted Therapy: Inhibiting Angiogenesis: What drug used? What does it bind and where? What does it inhibit? What results when combined with chemotherapy?
AVASTIN (first approved anti-angiogenesis drug for cancer)
- inhibits VEGF receptor
- (binds VEGF extracellularly to prevent it from binding its receptors)
- Combined w/ chemotherapy- it prolongs life ~5 months for patients w/ metastatic colorectal cancer
Chemotherapy drugs based on components of cell cycle machinery. 3 examples?
- Mitotic inhibitors (M) - TAXOL
- Topoisomerase inhibitors (S,G2)- ETOPOSIDE & more
- Antimetabolites (S) MTX-METHOTREXATE
Chemotherapy Drugs: Mitotic inhibitors:
What drug used?
What are 3 functions?
TAXOL
- -binds/inhibits a protein in cell division->stops division
- -Freezes microtubules (can’t perform cell division)
- -binds/blocks BCL-2 (apoptosis inhibitor)- & induces apoptosis
Chemotherapy Drugs: Antimetabolites
What drug used?
What function?
Adverse Effects?
Example?
METHOTREXATE (MTX)
- decreases purine synthesis (inhibits DNA synthesis)-
- Myelosupression & Neurotoxicity
5’-Fluorouracil (pyrimidine antagonist) inhibits thymine synthesis & DNA replication.
Used for XP patients- 5’ fluorouracil based cream
Chemotherapy Drugs: Topoisomerase Inhibitors
2 topoisomerase 2 inhibitor drugs:
1 topoisomerase 1 inhibitor drug:
Etoposide- TI2in- break DNA/cell death (S/G2 phase)
Doxorubicin- TI2in-Break DNA/helix unsealed (stops replication)
Camptothecin- TI1in- blocks rejoining
Alkylating Agents (antineoplastic/anticancer drugs)
What do they alkylate?
What function?
What is known as the “penicillin of cancer drugs”?
What does this drug form?
- Inhibit DNA TRANSCRIPTION
- replace Hydrogens with alkyl groups
- Inhibits DNA synthesis and triggers apoptosis
CISPLATIN- forms adduct of 2 guanine bases in DNA
- not specific in cell cycle
Autosomal dominant
DOMINANT inheritance pattern?
AD: disorder in every generation w/ equal number of males and females affected
The predisposition to getting cancer is DOMINANT
(ie: Rb inherited 1 bad gene, just needs one more hit– its DOMINANT because high disposition to getting cancer)
