Lecture 4,5 - Genetic Basis of Cancer Flashcards
Three Criteria for Cancer
Aggressive, Invasive, Metastatic
Benign Tumor
Does not have all three criteria for cancer but like has some of the features
Most Frequent Cancer Types
Prostate (PSA Test)
Lung (Catscan)
Breast (Mammogram)
Colon/Rectum (Colonoscopy)
Oral Cancer Frequency and Death rate, Risk of Diagnosis
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
Mutational MEchanisms of Carcinogenesis
1) spontaneous gene or chromosome mutation
2) mutagens or radiation (sun UV or treatment)
3) Tumor virus
4) inherited predisposition
What was the conclusion on Dental X Rays affect on cancer
Inconclusive becasue the study had sketchy data and was not significant numbers.
Tumor Viruses (two types)
RNA Tumor viruses - not seen in humans
DNA tumor viruses - v rare (HPV and Herpes)
What cancers does HPV and Herpes cause
HPV - Cervical and ORAL
Herpes - Kaposi Sarcoma
Genes Mutated in Cancer (and there traits)
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
Proto-Oncogenes examples discussed in class
Activation of EGFR (anything that causes this)
KRAS activation
BRAF activation
Cyclin D
Targeting Oncogenes vs Tumor Suppresor
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
Receptor Tyrosine Kinase Mutations that result in EGFR activation
Anything that pushes it together will result in cross phophorylation
Receptor becomes ligand independent and would be active
Two ways that results in increase EGFR path activation
EGFR overexpression - ton of Growth Factor receptor (RECEPTOR NOT GF)
ACtivating point mutations - causing ligand independent binding
Two therapeutic ways to target the EGFR activation
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
KRAS Function
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
Farnesyl Transferace Inhibition
Idea is to inhibit ras production in the first place so that it does not have this accumulation of always active
BRAF Function and Cancer relation
Activated after KRAS.
Can get mutated in kinase domain. It is an enzyme so we have powerful inhibits
Philadelphia Chromasome
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
Time and Function of each cell cycle stage
S phase - DNA synthesis (10h)
G2 - between S and M (4.5h)
M Phase - PMAT (.5h)
G1 Phase - between m and s (9h)
Importance of Phosphorylation in Cell Cycle
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
Checkpoints: (three types of damage, and where they arrest)
DNA Damage - Arrest in G1
Unreplicated DNA - Arrest in S
Improper Mitotic spindle assembly Arrest in M phase
premature progression causes genetic damage
Restriction Point
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
p53 Infromation
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
Treatment of Tumor with p53 muations
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
MDM2 importance
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
Loss of Restriction Point Control (3 Ways)
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
Diseases associated with each of the restriciton point control mutations
Cyclin D Overexpression - Breast Caner
Loss of p16 Function - Familial Melanoma
Loss of Rb Function - Retinoblastoma osteosarcoma
Oral Cancer Carcinoma Problem with percent chance and risk factors
p53 inactivation 50-60%
p16 Inactivation 80%
Cyclin D amplification 30-50%
Smoking tobacco use, betel use, HPV
Two Hit Model for Retinoblastoma
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
Ways to Lose Heterozygosity (thats not just a mutation double)
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
List of Tumor Suppressor Genes Discussed
p53,
P16
Rb
Inherited Colon Cancers (and rate)
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.
APC Pathway
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
The MMR pathway
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
Sporadic Cancer Colon (Chance, and two paths)
No Genetic History 70%
1) APC inactivation is 85%
2) 15% is MMR inactivation
these things just happen on their own
Multihid model of carcinogenesis
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
the Role of MMR in Sporadic Colon Cancer
Hypermethylation in path to cancer. You hypermetyhalte promotor of the MMR and therefoer you have again microsatellite instability and more mutaitons build up
BRAF mutations in the sporadic colon cancer
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?
