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BIOCHEMISTRY > EXAM2_L23_L24_Cancer_Biology_Genetics_of_Cancer > Flashcards

EXAM2_L23_L24_Cancer_Biology_Genetics_of_Cancer Flashcards

1
Q

What is Cancer?

A
  1. Genetic Disease (hereditary or spontaneous)
  2. Result from accumulation of somatic mutations clustered in one cell
  3. Loss of cell cycle control (g1,s,g2,m)> uncontrolled proliferation
  4. All cancer due to mutations passed to other cells
  5. Multi-factorial disease
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2
Q

What are the 1st and 2nd most common cause of death in the USA?

Who is at risk for cancer?

A

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
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3
Q

What are the 4 Classes of Tumors?
Where are each derived from?
Which one is most common?

A
  1. CARCINOMA (epithelial cells)- 90% malignant tumors
    - lung, prostate, breast, skin, colon
  2. SARCOMA (supporting- CT, BV,Fat, Muscle, Bone) 1%
  3. LYMPHOMA (Immune system cells) solid mass blood cells
  4. LEUKEMIA (blood-forming tissues-lymph & bone marrow)
    - large proliferation of malignant blood cells in bloodstream
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4
Q

What are the 4 major causes of cancer?

A
  1. Chemical
  2. Viruses (HPV)
  3. 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)
  4. Obesity
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5
Q

How common is it for humans to get cancer due to exposure to carcinogens?
What are some examples?

How do carcinogens work?

A

80% of Cancers due to exposure to carcinogens!

  • ie:
  • UVB- distorts DNA structure
  • X/Gamma rays- dsDNA breaks
  • Chemicals that interact directly w/ DNA
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6
Q 
Tumor Initiators vs 
Tumor Promoters (examples?)

What will cause cancer?

A

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

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7
Q 
Tumor viruses
how common?
What seen in RNA viruses?
What seen in DNA viruses?
ex of DNA virus?
A

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

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8
Q

HPV one-two punch

What two proteins does HPV encode?
What do each inhibit?

A

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

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9
Q 
HPV Vaccine? 
Generic name?
What is it?
What is it made of?
How does it work?
A

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
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10
Q

Genetic Mutations: what types?
Where mostly found?
what two types of genes affected by mutations?

A
  • inherited or spontaneous
  • DNA repair enzymes or signal transduction pathway proteins
    1. Proto-oncogenes
    2. Tumor suppressor genes
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11
Q

Proto-oncogenes & onchogenes

How do proto-oncogenes become oncogenes?
3 ways

A

proto-oncogenes = normal function

  • oncogenes function when they shouldn’t
    • gain of function mutations
  1. point mutation (altered product)
  2. Amplification (gene overexpression)
  3. Gene arrangement/translocation
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12
Q

Proto-oncogenes converted to oncogenes:

POINT MUTATIONS:

A

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
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13
Q

Proto-oncogenes converted to oncogenes:

GENE AMPLIFICATION:

A

-DNA replication error increases # gene copies of a TF in a chromosome:

  1. MYC gene amplified on chromosome
  2. MYC mRNA transcripts increased
  3. 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
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14
Q

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?

A

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

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15
Q 
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?

A

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

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16
Q

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?

A
  1. RTK
  2. RAS GTPase
  3. Transcription factor MYC

Increase CYCLIN D- > Allows cells to cross restriction point

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17
Q

RTK

Two types that are OUT OF CONTROL!

A

Receptor Tyrosine Kinases
Truncated RTK- continuously send growth signal w/o ligand

Amplified RTK- HYPER signal w/ small amounts of ligand

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18
Q

What two types of genes do mutations affect?

A
  1. Proto-oncogenes

2. Tumor suppressor Genes

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19
Q

Loss of Function Mutations
TSG= Tumor suppressor Gene

TWO Examples of TSG’s

A

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!
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20
Q

What is normal and mutated function of p53

A

p53 normally STOPS cell cycle, DNA repair, apoptosis

Mutated- p53 inactive- NO DNA repair, apoptosis. Cant STOP cell cycle

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21
Q

TUMOR suppressor gene RB

Normal and mutated RB function

A

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

22
Q

What disease is caused by inheritable mutation of RB?

A

Retinoblastoma
Familial-
Sporadic

23
Q

What is the knudsen’s “two-hit” Hypothesis?

Spontaneous Vs inherited

A

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)

24
Q

Li-Fraumeni Syndrome
What defect of?
How common?
What happens if you have it?

A

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
25
Q

DNA repair defects in humans

What genes? Function? Familial Cancer?

A

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

26
Q 
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?
A

Hereditary Nonpolyposis Colon Cancer (HNPCC)
“LYNCH SYNDROME”
-MSH2,MLH1 Gene Mutations (DNA repair mechanism)
-Autosomal Dominant
-presents w/

27
Q

BRCA1/BRCA2 Mutations
What type of genes?
What cancer linked with them?
If BRCA1/2 mutated How common develop breast/ovarian cancer?

A

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

28
Q 
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?
A 
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

29
Q 
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?
A

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)

30
Q

How does neurofibromin protein normally function?

What happens when NF1 Mutated?

A

NF1 is a GTPase Activating Protein (GAP)
-NF1 Deactivates RAS (by stimulating RAS GTPase)
-
Mutated NF1 can’t deactivate RAS –> Cancer

31
Q 
FAP
APC (adenomatous polyposis coli gene)
How does it present?
Why so serious?
Average age?
Treatment?
A
  • 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
32
Q 
APC protein
What is it called?
What classified as?
Part of what pathway
Normal Function of APC?
A

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)
33
Q

Beta-Catenin

A
  • 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

34
Q

WNT
What is it? What does it do?
What is APC?

A

Signaling molecule that binds GPCR

-Inhibits APC & STOPS B-Catenin degradation

APC- “adenomatous Polyposis Coli” (TSG)- degrades Bcatenin

35
Q

WNT Signaling of APC and B-Catenin:

What is normal function without signal?

Function With growth signal?

Function With mutated APC cells?

A

WNT- No growth signal:

  1. “destruction complex” DEGRADES B-Catenin
  2. GF gene transcription INHIBITED- NO PROLIFERATION

WNT-w/ Growth signal:

  1. “Destruction Complex” is DEACTIVATED
  2. Beta-Catenin enters nucleus & ACTIVATES Transcription of Growth associated Genes.= PROLIFERATION

WNT w/ Mutated cells:

  1. no signal
  2. APC mutation permanently INHIBITS destruction complex
  3. B-catenin ACTIVATES transcription gene factors
  4. Cell Proliferation (even w/o growth signal)
36
Q

WNT Signaling Summary:
No Growth Signal:
w/ Growth Signal bound to GPRC:
Mutated APC:

WHAT SECRETES WNT GROWTH SIGNAL?

A
  1. no growth signal= degraded B-catenin- no proliferation
  2. growth signal bound= B-catenin in nucleus= Proliferation
  3. Mutated APC= No destruction complex= Proliferation

Stromal cells of colon secrete WNT growth signal

37
Q

Cell migration/Polyp formation of colon :
How do colon cells replicate and have continuous turnover?

What happens with mutated APC?

A
  1. Stromal cells secrete GF: WNT (binds GPCR on colonic stem cells)
  2. Colon crypts replicate and differentiate as migrate upward
  3. WNT signal decreases as they get further away (causes division to stop but continued differentiation until sloughed off at top of crypt)
  4. 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)

38
Q

OBESITY & CANCER RISK

What happens to adipocytes?
What decreases risk? recommended amount?

A

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)

39
Q 
7 Tumor suppressor genes mutated in human cancers
What genes?
What pathway affected?
What familial cancer syndrome?
Inheritance pattern?
A
  1. RB (restriction point G1 control)-Retinoblastoma
  2. TP53 (DNA damage/apoptosis)-Li-Fraumeni
  3. APC (prevents B-Catenin Growth signal)-FAP
  4. NF1 (inhibits RAS signal)-Neurofibromatosis type 1
  5. BRCA1,2 (DNA break repair)-Familial breast cancer
  6. MSH2,MLH1 (DNA mismatch repair) HNPCC LYNCH
  7. XP Genes (pyrimidine Dimer repair) Xeroderma pigmentosa (RECESSIVE)- all others are DOMINANT
40
Q

Gain of function mutations:
What kind of genes?
What mutation required?
Examples?

Loss of function Mutations:
What kind of genes?
What mutation required?
Examples?

A

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)

41
Q

Targeted Therapy Treatments:

3 anticancer strategies?

A
  1. Immunotherapy- (antibodies against tumor cells)
  2. Inhibition of cancer-promoting proteins
  3. Inhibition of Angiogenesis (Prevent BV growth for tumor)
42
Q 
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?
A

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
43
Q

Immunotherapy: RITUXAN
What does it bind?
What does it inhibit and induce?
What does it treat? when approved?

A

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
44
Q

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?

A

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)
45
Q 
Targeted Therapy:
Inhibiting Angiogenesis:
What drug used?
What does it bind and where?
What does it inhibit?
What results when combined with chemotherapy?
A

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
46
Q

Chemotherapy drugs based on components of cell cycle machinery. 3 examples?

A
  1. Mitotic inhibitors (M) - TAXOL
  2. Topoisomerase inhibitors (S,G2)- ETOPOSIDE & more
  3. Antimetabolites (S) MTX-METHOTREXATE
47
Q

Chemotherapy Drugs: Mitotic inhibitors:
What drug used?
What are 3 functions?

A

TAXOL

  1. -binds/inhibits a protein in cell division->stops division
  2. -Freezes microtubules (can’t perform cell division)
  3. -binds/blocks BCL-2 (apoptosis inhibitor)- & induces apoptosis
48
Q

Chemotherapy Drugs: Antimetabolites
What drug used?
What function?
Adverse Effects?

Example?

A

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

49
Q

Chemotherapy Drugs: Topoisomerase Inhibitors

2 topoisomerase 2 inhibitor drugs:
1 topoisomerase 1 inhibitor drug:

A

Etoposide- TI2in- break DNA/cell death (S/G2 phase)

Doxorubicin- TI2in-Break DNA/helix unsealed (stops replication)

Camptothecin- TI1in- blocks rejoining

50
Q

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?

A
  • 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

51
Q

Autosomal dominant

DOMINANT inheritance pattern?

A

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)

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