Molecular Carcinogens & Clinical Correlates Lecuture

Question 1

What are the 6 hallmarks of malignancy?

Answer 1

1) Evading Apoptosis
2) Self-sufficiency in growth signals (oncogenes)
3) Insensitivity to antigrowth signals (tumor suppressor defects)
4) Tissue invasion and metastasis
5) Limitless replicative potential (telomerase)
6) Sustained angiogenesis (VEGF)

Question 2

Top 5 Cancer Incidence for Males

Answer 2

1) Prostate
2) Lung
3) Colon & Rectum
4) Urinary Bladder
5) Melanoma of skin

Question 3

Top 5 Cancer incidence for Females

Answer 3

1) Breast
2) Lung
3) Colon and rectum
4) Uterine
5) thyroid

Question 4

Top 5 Cancer Mortality for Males

Answer 4

1) Lung
2) prostate
3) Colon and rectum
4) pancreas
5) Liver & bile duct

Question 5

Top 5 Cancer Mortality for Females

Answer 5

1) Lung
2) Breast
3) Colon and rectum
4) Pancreas
5) Ovary

Question 6

2 steps to carcinogenesis

Answer 6

1) initiation of mutation (irreversible) - NOT self-sufficient for tumor formation
2) Promotion (reversible) affects ONLY “initiated” cells, time and dose-dependent

Question 7

2 types of initiators

Answer 7

1) Direct-acting carcinogens (ie require no metabolism… like alkylating agents)
2) Indirect-acting carcinogens (ie DO require metabolism… THUS enzyme polymorphisms likely play a big role in how each person responds to exposure… examples are afltatoxin, plant and microbial products, polycyclic aromatic hydrocarbons)

Question 8

What are 4 “enablers” of cancer

Answer 8

1) Genome instability = defects in DNA repair
2) Reprogramming Energy Metabolism (warburg effect)
3) Tumor-promoting inflammation (growth factors, survival factors, matrix matelloproteases)
4) Evading immune system/ Destruction

Question 9

What is xeroderma pigmentosa

Answer 9

DNA repair defect –> genomic instability

defect in nucleotide EXCISION repair (UV-light induced pyrimidine dimers that need to be fixed)

Question 10

What is Hereditary Nonpolyposis Cancer Syndrome (HNPCC)?

Answer 10

defect in MISMATCH repair

MLH1 & MSH2 gene defects resulting in “microsatellite instability” resulting in replication error phenotype

80% lifetime risk of CRC, also ovarian and endometrial cancers are a risk as well

Note - 15% of sporadic cancers can cause these MSH2 and MLH1 mutations as well

Question 11

What are 3 different syndrome characterizted by defects in Homologous Recombination of DNA repair

Answer 11

1) Ataxia telangectasia (ATM) - usually can sense double stranded breaks! (Cerebellar ataxia & immunodeficiency!)
2) Bloom syndrome - mutation in a BLM helicase that normally fixes homologous recombination (developmental defects aka fail to “bloom” correctly)
3) Fanconi Anemia - several genes involved in double strand break repair! (includes BCRA2)

Question 12

How do tumor cells induces limitless replicative potential?

Answer 12

1) inactivate senescence signals
2) evade mitotic crisis by activating telomerase!!!
3) contains stem-cells for self-renewal

Question 13

To use trastuzumab (tras”2”zumab) to beat breast cancer… what receptors are required to be present on the surface of the cell? How do cells acquire resistance

Answer 13

ErbB2/neu/HER2 (epidermal growth factor family)!

Patients with a PTEN deficiency might become resistant to it! (Cowden syndrome)

Question 14

What tyrosine kinase does Lapatinib stop?

Answer 14

HER2/ErbB2 & EGFR/HER1

Question 15

What other tyrosine kinase also binds Her2/neu/ErbB2?

Answer 15

Per”2”zumab… can be used with trastuzumab

Question 16

How does a defect in NF-1 effect cell signaling?

Answer 16

NF-1 is a GTPase activating protein (GAP)… so with a mutation… GAP is not induced… leaving RAS in the “activated” position to promote downstream PI3K and MAPK pathways

Question 17

What is a common mutation in skin melanoma?

Answer 17

B-RAF in 60-70% of melanomas!

Question 18

What is an important regulator of cell cycle progression from G1 to S phase? And how is it regulated?

Answer 18

Retinoblastoma! (RB gene)… it is active in the HYPOphosphorylated state… thus PREVENTING cell cycle progression

Cyclin D acts to phosphorylate RB which inactivates it… releasing E2F resulting in transcription!

BUT Cyclin D is also inhibited by p16-INK4a (p16-INK4a gets stimulated by TGF-b, p53 etc)…

Question 19

How does HPV cause genetic carcinogenic changes in RB?

Answer 19

Especially the more “cancerous” types (ie HPV 16 & 18) result in E7 which binds RB releasing E2F to induce transcription! (E7 results in decreased p21 –> activated cyclinD/CDK–> RB gene destroyed)

Question 20

How does HPV cause genetic carcinogenic changes in p53?

Answer 20

E6 binds and inhibits p53 directly… degrading it… AND it activates TERT (telomerase activity gene)

Question 21

What is a super dooper important inhibitor of the cell cycle? (CDKI)

Answer 21

p16/INK4a! it gets inactivated in many cancers!

Question 22

Intrinsic Apoptosis pathway

Answer 22

damaging insult to DNA –> pro-apoptotic genes (bik, bid, bim aka the all BH3 family) overcome BCL genes –> BAX & BAK poke holes in the mitochondria –> cytochrome C leaks out –> activates caspase9 –> Activation of “effector caspases” 3, 6, 7!

Question 23

Extrinsic Apoptosis Pathway

Answer 23

FAS-FASL or TNF-alpha bind (CD95) –> pro-caspase 8 –> activator caspases!

Question 24

How does follicular cell lymphoma evade apoptosis?

Answer 24

recall it is BCL2+… therefore it is a 14;18 translocation puting BCL2;IGH! so which such anti-apoptotic induction… the pro-apoptotic genes cannot overcome it!

Question 25

What is the VEGF inhibitor that we gotta know and what is the good read-out for it?

Answer 25

bevacizumab! and hypertension implies that its actually working!

Question 26

What is the hallmark change allowing for metastasis?

Answer 26

changes in cell-cell interaction such as E-Cadherin!

Question 27

What is the drug to treat CML?

Answer 27

CML = philly chromosome 9;22… the drug targets the BCR-ABL fusion protein product and its name is… Imatinib (aka Gleevec)