Lecture 4,5 - Genetic Basis of Cancer

Question 1

Three Criteria for Cancer

Answer 1

Aggressive, Invasive, Metastatic

Question 2

Benign Tumor

Answer 2

Does not have all three criteria for cancer but like has some of the features

Question 3

Most Frequent Cancer Types

Answer 3

Prostate (PSA Test)
Lung (Catscan)
Breast (Mammogram)
Colon/Rectum (Colonoscopy)

Question 4

Oral Cancer Frequency and Death rate, Risk of Diagnosis

Answer 4

Frequency 50,000 (48,000) a year, and 10,000 deaths
lifetime risk of diagnosis 1% and .3% risk of dying
Incidence double in men

Question 5

Mutational MEchanisms of Carcinogenesis

Answer 5

1) spontaneous gene or chromosome mutation
2) mutagens or radiation (sun UV or treatment)
3) Tumor virus
4) inherited predisposition

Question 6

What was the conclusion on Dental X Rays affect on cancer

Answer 6

Inconclusive becasue the study had sketchy data and was not significant numbers.

Question 7

Tumor Viruses (two types)

Answer 7

RNA Tumor viruses - not seen in humans

DNA tumor viruses - v rare (HPV and Herpes)

Question 8

What cancers does HPV and Herpes cause

Answer 8

HPV - Cervical and ORAL

Herpes - Kaposi Sarcoma

Question 9

Genes Mutated in Cancer (and there traits)

Answer 9

Proto-oncogenes - gain of funciton, heterozygous
Tumor Suppressor Genes - loss of funciton must be homozygous
mutator genes - leads to an increase amount of mutations must be homozgous also to facilitate mutations

Question 10

Proto-Oncogenes examples discussed in class

Answer 10

Activation of EGFR (anything that causes this)
KRAS activation
BRAF activation
Cyclin D

Question 11

Targeting Oncogenes vs Tumor Suppresor

Answer 11

oncogenes- imilted number of mutations so target for drug therapy
tumor suppresor - large number of mutations not good for drug therapy
gene therapy target to like fix the DNA

Question 12

Receptor Tyrosine Kinase Mutations that result in EGFR activation

Answer 12

Anything that pushes it together will result in cross phophorylation
Receptor becomes ligand independent and would be active

Question 13

Two ways that results in increase EGFR path activation

Answer 13

EGFR overexpression - ton of Growth Factor receptor (RECEPTOR NOT GF)
ACtivating point mutations - causing ligand independent binding

Question 14

Two therapeutic ways to target the EGFR activation

Answer 14

1) antibodies to coat outside domain receptors
2) inside domain, can target the kinase inhibitors called TGFRTKI to inhibit the tyrosine kinase
Another good way is to target Increase EGFR with Iressa

Question 15

KRAS Function

Answer 15

not an enzyme, molecular switch binding GTP
activated once receptor binds. RAS holds GTP and then it becomes GDRP when inactive
with mutations then it may get stuck active
Ras mutation can inhibit the GTPase so activiety is always on

Question 16

Farnesyl Transferace Inhibition

Answer 16

Idea is to inhibit ras production in the first place so that it does not have this accumulation of always active

Question 17

BRAF Function and Cancer relation

Answer 17

Activated after KRAS.

Can get mutated in kinase domain. It is an enzyme so we have powerful inhibits

Question 18

Philadelphia Chromasome

Answer 18

a peice of Chromasome 9 swaps with 22 and shorter 22 has abnormal BCR-Abl gene
Results in CML (chronic myelogenous leukemia)
Treat with gleevac

Question 19

Time and Function of each cell cycle stage

Answer 19

S phase - DNA synthesis (10h)
G2 - between S and M (4.5h)
M Phase - PMAT (.5h)
G1 Phase - between m and s (9h)

Question 20

Importance of Phosphorylation in Cell Cycle

Answer 20

Target of CDK complexies is to phosphorylate proteins
A common control is regulation by degredation of certain things
So the phosphorylation of something may lead to its degredation

Question 21

Checkpoints: (three types of damage, and where they arrest)

Answer 21

DNA Damage - Arrest in G1
Unreplicated DNA - Arrest in S
Improper Mitotic spindle assembly Arrest in M phase
premature progression causes genetic damage

Question 22

Restriction Point

Answer 22

Cells that go past this restricition point in LATE G1 are commited to enter S phase, and they will divide
So this is tightly regulated

Question 23

p53 Infromation

Answer 23

Tumor Suppresor Gene, participates in checkpoint conrol
Damage to DNA results in stablizing p53
Which transcribes p21 in G1 to sit on CDK complex (stop in g1)
You could also arrest in G2 but diff path

Question 24

Treatment of Tumor with p53 muations

Answer 24

cannot do radiation, because the pathway that ardiation goes is messed up there wont be apoptosis. So resistance to radiation
p53 is a tetramer that syntehsizes various things

Question 25

MDM2 importance

Answer 25

Enzyme that adds ubiquitin to p53 for degredation. If there is DNA damage then MDM2 does not function and therefore p53 remains stable to act

Question 26

Loss of Restriction Point Control (3 Ways)

Answer 26

Cyclin D - Overexpression. You get more phosphorylation of the Rb so you have more expression of E2F therefore its always on. This is a proto-oncogene loss of Rb function - E2F is never inhibited and therefore the cell will go to S phase uncontrolled Loss of p16 Function - sits on Cyclin and CDK4 and inhibits it so it doesnt work. When you dont have it then you have less regulation and so E2F levels go up

Question 27

Diseases associated with each of the restriciton point control mutations

Answer 27

Cyclin D Overexpression - Breast Caner Loss of p16 Function - Familial Melanoma Loss of Rb Function - Retinoblastoma osteosarcoma

Question 28

Oral Cancer Carcinoma Problem with percent chance and risk factors

Answer 28

p53 inactivation 50-60% p16 Inactivation 80% Cyclin D amplification 30-50% Smoking tobacco use, betel use, HPV

Question 29

Two Hit Model for Retinoblastoma

Answer 29

Needs two mutations for the issue Sporadic - no family history so need two mutations to occur Two results in loss of heterozygosity tumor is in one eye Hereditary - only needs one more bad mutations tumors are seen in both eyes. Early onset

Question 30

Ways to Lose Heterozygosity (thats not just a mutation double)

Answer 30

Mitotic Missegregation - problem in anaphase. Get one cell with three chromatid one with three. Then the one with three does random dies. so then a chance you get two of the same mutated Mitotic Recombination - due to recombination and then seperation resulting in two bad parts

Question 31

List of Tumor Suppressor Genes Discussed

Answer 31

p53, P16 Rb

Question 32

Inherited Colon Cancers (and rate)

Answer 32

25% of colon cancer is with family history without knowing mutation 1) FAP - soooo many polyps gurantee of colon cancer. From a loss of function mutation in tumor suppresor in the APC gene 2) Lynch Syndrome DNA mismatch repair mutation (in a MMR) results in an inabiliyy to repair mismatch and destabalizes resulting in increase amount of mutations. also KRAS mutations, APC normal, Beta Catenin Mutation.

Question 33

APC Pathway

Answer 33

Marks Beta Catenin for degredation. It is a tumor suppresor. Without it you will increase beta catenin in the wnt pathway and therefore you would have more poliferation

Question 34

The MMR pathway

Answer 34

Deletion in the mismatch repair gene. LEads to unstable minisatellites. When unable to get repair then muations will build up and you could get them on an oncogene or tumor suppresor

Question 35

Sporadic Cancer Colon (Chance, and two paths)

Answer 35

No Genetic History 70% 1) APC inactivation is 85% 2) 15% is MMR inactivation these things just happen on their own

Question 36

Multihid model of carcinogenesis

Answer 36

Total accumulation of mutations determine tumor properties Must have many mutations to mess with all cell cycle ORder Does not matter Need 4-5Mutations for Colon Cancer

Question 37

the Role of MMR in Sporadic Colon Cancer

Answer 37

Hypermethylation in path to cancer. You hypermetyhalte promotor of the MMR and therefoer you have again microsatellite instability and more mutaitons build up

Question 38

BRAF mutations in the sporadic colon cancer

Answer 38

Is a protooncogene and can be seen in the contribution to sporadic tumors of colon cancer Braf muations are seen in most sporadic tumors but not in lynch syndrome patients hmmmmm?