18th lecture (cancer development, oncology) Flashcards
what are the genetic and epigenetic alterations occur that lead to cancer?
Epigenetic: not imprinted into the genome and more about regulation.
Genetic: - oncogenes - tumor suppressor genes - DNA repair genes - Telomer and telomerase Epigenetic alterations: - DNA-methylation - Micro-RNA expression
what are the oncogenes and protooncogene?
oncogenes are genes that have normal function called protooncogenes.
To become neoplastic they have to have a protooncogen - oncogene alteration.
In all cells with normal function: protooncogenes
Any alteration that activates them = oncogene activation.
what are some of the alterations that can activate a protooncogenes?
- point mutation (continuously activated independently from its promoter)
- Translocation (changing the promoter)
- Translocation (but the break occurs in the coding axons)
- Geneamplification
Example of a point genetic mutation?
Epidermal growth factors receptor (EGF) point mutation. Normally EGFR dimerize when they take up the ligand and phosphorylation occurs of downstream proteins, activating different pathways.
in the protooncogene - oncogene transformation single point mutation of the receptor in the cytoplasmic end causes autonomous activation and phosphorylation of the downstream pathways, WITHOUT the EGF.
Cell cycle, gene transcription, cell division occurs without regulation.
Example of the translocation genetic mutation? (promoter exchange)
In chromosome 14: immunoglobulin heavy chain gene is coded
In chromosome 18: the Bcl2 gene is coded.
The promoter/enhancer of the immunoglobulin gene joints to the Bcl2 gene and thus there is an overexpression of Bcl2.
Normally the cell damage causes BAX-BAX BUD-BUD homodimer activate cytochrome C and caspase and apoptosis occurs. (intrinsic path of apoptosis).
In pathological conditions: Bcl2 forms heterodimers with the BAX and BUD suspending the apoptosis.
Example of the translocation genetic mutation that occurs when there is a break in the gene itself instead of the promoter.
9-22 translocation: characterizes chronic myeloid leukemia Breakpoint cluster region (BCR) in #22 ablezone gene (ABL) #9
the breaking regions of the gene, depending on the region where the breakpoint occurs it could be chronic or acute cancer.
This new oncoprotein activates different pathways; the results is apoptosis blocking, cell proliferation.
Example of geneamplification?
- No problem with the gene itself, its just present at higher amounts.
C-MYC and HER2 (amplified during breast cancer)
the segment on the chromosome that represents a certain gene is bigger then it should be
They can also be present outside of the chromosome as double minutes; Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma.
Define tumor suppressor genes and their importance to genetic alteration leading to cancer.
Important in controlling the normal way gene activation, and if it is broken, it can lead to tumors.
In contrast to oncogene/protooncogenes which are activating tumor suppressor genes are silencing.
what are the methods/pathways of tumor suppressor gene silencing?
- loss of heterozygosity (there is normally a paternal and maternal allele and one could be silenced, the other could still work and cancer will not develop, (bilateral inactivation of the gene is needed) loss of heterozygosity is just on the road to cancer but cancer has not yet developed.
- one allele is point-mutated causing a missence mutation, thus the protein is non-functional. (deletion, mutation)
- Hypermethylation; This is more of an epigenetic mutation. The promoter is methylated suspending the expression of the gene.
- Transdominant gene; one is a normal allele and the other is mutated. The mutated one makes a complex with the unmutated, silencing it.
- Haplo-insufficiency: There are certain tumor suppressor genes where both alleles are needed for the proper function of the gene. One could be suppressed.
what ways could tumor suppressor gene inactivation occur?
hereditary and sporadic:
- Heriditary: one allele is affected and they only need one “hit” to the other allele to develop cancer.
- Sporadic: both alleles need to take a “hit” and mutate and cause cancer.
KNUTSON theory of tumor development: double hit of the tumor suppressor gene to cause inactivation and cancer.
Describe the retinoblastoma tumorsuppressor gene in cancer development.
The cell cycle (G1, S, G2, M) is progressed by cyclin dependent kinases) There are cyclin dependent kinase inhibitors. There may be a disbalance between cyclin dependent kinases and their inhibitors.
There is the G1/S checkpoint, which is progressed by CDK 4,6 and cyclin-D which if they dimerise they phosphorylate the RB and remove its inhibition of the E2F so transcription can take place.
Normally RB inhibits the E2F.
In a tumor the RB could be silenced and thus cancer can develop, as the cell cycle is no longer regulated.
what are the hereditary neoplasms and sporadic neoplasms in RB?
Hereditary neoplasms: - retinoblastoma, osteosarcoma Sporadic neoplasms: - Retinoblastoma, - osteosarcoma, - breast cancer - colon cancer
Describe the p53 gene in cancer development.
p53 is controlling the genome. If the p53 detects DNA damage it will detect from MDM2 and block CDK4,6 and Cyclin-D dimer, and thus blocking the retinoblastoma activation.
The cell will die, because its better to do so then to carry a mutation on.
If the p53 suffers a mutation and the DNA does too, it could carry on the mutation and multiply.
what are the hereditary neoplasms and sporadic neoplasms in p53?
Hereditary:
- Li-Fraumeni-syndrome
Sporadic neoplasm
- most human cancers
Wherever the p53 is involved the disease is aggressively progressive.
Describe the APC gene in cancer development.
adenomatosus polyposis coli
if mutated the patient has several adenomas in the intestine that could develop into cancer.
it involves the WNT signalling pathway.
Normal cell-proliferation needs B-katenin-TCP dimers which activate the transcription factor. A WNT signal to the cell will causes APC activation and dimer formation and transcription will occur.
If inactivated then APC forms a destruction complex and destroys the B-katenin and no activation occurs.
Mutation of the APC means continuous activation of the B-katenin
