cancer continued Flashcards
Factors that affect cancer
Genetic and environmental
Genetic factors example
-BRCA mutation
-BRCA is a tumour suppressor mutation and both BRCA1 and BRCA2 cause a 5x chance of developing breast cancer in woman and 10-30x chance of developing ovarian cancer
Environmental factors example
The frequency of Burkitt’s lymphoma is much higher in individuals in central africa than those who have immigrated to the USA.
Tobacco causes
24% in lung kidney and bladder cancer
Diet low in veg, high in salt and nitrates
5% of stomach and esophogus
diet high in fat and low fibre
also includes fried and broiled foods
37% of bowel, pancreas, prostate and breast cancer
Tobacco and alcohol
2% of mouth and throat
Tumor initiators
They are mutagens that are either physical or chemical
-Many chemicals in the liver are unreactive but are converted into mutagens via cytochrome P450 metabolism and would not cause cancer if just given to cells
E.Mutagens
Diazomethane, aromatic amines, nitrosamines
Test for mutagens
Ames test
Tumor promoters
They promote changes to the intracellular or extracellular environment of the damaged cell to promote tumor formation
-They require tumor initiators to induce tumor
-Chronic inflammation and repair are sufficient to promote tumor formation of mutated cells as the chemicals stimulate damaged cells to grow
E.Tumor promoter
Phorbol esters are a class of compounds that activate Protein Kinase C
-This is a kinase that is activated by elevated calcium levels and Diacyl glycerol and promotes cell growth
Viruses role in cancer history
Peyton rouse showed that the Rous sarcoma virus that was extracted from chicken tumors could transmit cancer to health chickens
-the v-src gene in the RSV is a oncogene that pushes cells into uncontrolled mitosis and transformation
how much cancer do viruses cause
20% of all cancers
HPV
-Human Pappiloma virus
-They infect cutaneous and mucosal epithelia
-HPV 16 is a HR (high risk genotype) that causes 55% of cervical cancers
-HPV 18 causes 18% of cases of cancer from HPV
classes of genes involved in cancer
-Oncogenes
-Tumor suppressor genes
-DNA maintanence genes
Oncogenes
-Start as protooncogenes that promote cell survival
-Mutate into oncogenes that stimulate unregulated proliferation
-Only needs one mutated copy
Tumor suppressor genes
Genes that when mutated, lose function and this loss of function pushes cells towards cancer phenotype
-Needs both copies to be mutated
E. Viral transduction of oncogenes
-proto-oncogene c-SRC is transduced by RSV and it is a tyrosine kinase that is constitutively activated by virus
-v-src is an oncogene that pushes the cell into transformation
Ras proteins
They are coded byproto-oncogenes that are mutated in cancer
-3 genes encode for them: HRas, KRas, NRas
-They are GTPases that function as molecular switches that regulate survival and proliferation pathways
-aMutations typically occur at 12, 13 and 61 codons
Regulation of K-Ras
They have inherent GTase activity that degrade GTP into GDP to become inactive
-GTPase-activating proteins (GAPS): they increase the rate of GTP hydrolysis to GDP which switches it off
-Guanine nucleotide exchange factors (GEFs): facilitate the swopping of GDP for GTP in the G-protein which results in activation
Mechanisms for conversion of proto-oncogenes into oncogenes
-Point mutations increasing the activity of the protein (Ras)
-Gene amplification events may result in extra copies of the gene (Myc oncogene)
-Chromosomal rearrangements may create a constitutively active fusion gene product or place the gene downstream of a promoter which results in dysregulated expression ( BCR-ABL1)
Master cell regulator
-P53
-It responds to DNA damage and stress by controlling cell cycle, DNA repair, and apoptosis
-When activated, it acts as a transcription factor for may targets which changes due to context and type of stress
DNA damage to P53
-Mutations in TP53 gene which causes loss of p53 tumor suppressor function
-P53 is regulated by MDM2 which targets the protein for degredation and suppresses transcription
-DNA damage releases the P53 from MDM2 and causes the P53 to migrate to the nucleus to act as a transcription factor
-Mutations result in loss of tumor suppressor function
Retinoblastoma gene product
It regulates the cell cycle by acting as a checkpoint inhibitor that prevents dysregulated proliferation by preventing cell from entering S phase
-pRB binds to TF E2F which prevents transcription of genes that push cell into S phase
-It is phosphorylated and inactivated by an active CDK4-cyclin D complex which is inactivated by p16
-Cancer cells inactivate this gene or overexpress CDK4-cyclin D
HPV effect on p53 and pRB
-E6 and E7 proteins bind to p53 and pRB respectively
AKT effect on cancer
-It is a kinase that causes increased glucose uptake and overall metabolic function when mutated
this provides increased energy for cancer
