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WEEK 22:
Molecular basis of cancer:
| Question | Answer |
|---|---|
| cancer cell | divides continuously and inappropriately becoming immortal where it no longer maintains original function and loses its differentiation with some being able to spread to other sites |
| features of cancer (5) | proliferation (grow independently of external signals), immortality (avoid senescence/ telomere shortening), avoiding cell death (apoptosis blocked), angiogenesis (sustain nutrients), and metastasis (move to other site) |
| driver mutations | mutations which affect regulation of apoptosis, proliferation and immortality leading to cancer |
| passenger mutations | all other mutations that do not promote cancer |
| sequential mutations | give clones of a cell a growth advantage |
| cancer is what disease | clonal and multihit-multistep-multibiological process disease |
| gain of function mutation (3) | occurs due to overexpression and amplification of gene which changes regulatory regions, or point mutations, or fusions |
| loss of function mutation (3) | occurs due to point mutations, deletion with frameshift, or loss of allele |
| ways to identify cancer (2) | whole genome analyses and finding genes commonly damaged in cancers |
| familial syndromes | rare but help identify important cancer genes eg in retinoblastoma, colon cancer, and breast cancer |
| retinoblastoma | rare childhood tumour which arises in precursors of photoreceptor cells and is treated by radiotherapy or surgery |
| difference between familial and sporadic cases of cancer | familial cases are bilateral and associated with other tumours (mainly osteosarcomas) whereas sporadic cases are unilateral |
| two hit hypothesis for retinoblastoma in familial and sporadic cancer cases | found familial is caused by single random somatic event and sporadic requires two random somatic events |
| which gene in two hit hypothesis is responsible for retinoblastoma | RB gene identified for retinoblastoma |
| retinoblastoma phenotype | dominant at level of whole organism |
| phenotype of mutant allele in retinoblastoma | recessive at cellular level (need both) |
| since is it highly unlikely for sporadic mutation to inactivate both copies by 2 successive mutational events in retinoblastoma, the second mutation can occur by | mitotic recombinization or associated with loss of heterozygosity (LOH) for region containing Rb gene |
| cell cycle control checkpoints (4) | restriction point, G1, G2, and M |
| restriction point of cell cycle | go-no-go signal, cell requires growth signals to pass this checkpoint where beyond this, cell divide |
| G1 of cell cycle control | DNA damage checkpoint, entrance to S blocked if DNA damaged |
| G2 of cell cycle control | checks if replication is complete |
| M of cell cycle control | checks if chromatids are properly assembled on spindle involving Rb and p53 |
| proteins eg p53 | can trigger cells to enter apoptosis if cell cycle/ DNA synthesis fails |
| role of TS genes | detect errors, mediate repair, inhibit replication or mediate entry to apoptosis (so if error repaired leads to proliferation but it error not repaired leads to apoptosis) to prevent cancer eg p53 |
| oncogenes | mutated/ occasionally viral forms of genes (eg EGFR) involved in secreted growth factors (eg PDGF-B), cell surface receptors (EGFR), signal transduction components (RAS), or transcription factors (eg myc) which help proliferation |
| TS genes and oncogenes in cancer | oncogenes = uncontrolled proliferation and TS genes damaged so cannot stop damaged cells from moving on in cell cycle |
| deletions or point mutations in EGFR result in | constitutively active receptor eg NSCLC |
| cytogenetics of oncogenes (translocation) | chromosomal rearrangements creating a novel gene which is common in haematologic tumours and sarcomas |
| Bcr-Abl of oncogenes (translocation) | ABL on chromosome 9 fuses with BRC (breakpoint cluster region) locus on chromosome 22 producing a novel protein kinase acting on multiple downstream signaling pathways |
| Burkitts lymphoma oncogenes (translocation into transcriptionally active chromatin) | occurs when MYC gene is placed in a region of chromatin that is transcribed at a high level in antibody producing B cells (also associated with DNA translocations but doesnt create a fusion protein) |
| relationship between familial cancer and oncogenes | rarely associated as in the germline their action would be dominant and mutations would disrupt normal embryonic development leading to miscarriage |
| sustained angiogenesis | provide nutrients and O2 from vasculature needed for cell function and survival |
| VEGF | many cancers express VEGF which induces angiogenesis (new vessel growth) and promotes endothelial precursor cell formation in bone marrow (this is needed for cancer cells to grow) |
| appearance of vasculature due to cancer | disorganised due to imbalance of signals for growth v differentiation and leaky due to imperfect cell-cell junctions |
| metastasis and invasion of tissue mechanism (4) | loss of adhesion (delamination eg E-cadherin loss), activation of endogenous metalloproteinases. Invasion of leaky blood vessels (or lymph system) and flows in blood where few survive due to immune surveillance (aka epithelial-mesenchymal-transition, EMT) |
| secondary tumours | cells move to part of body where environment is suitable or capillary beds where tumour cells are larger and tend to get stuck in capillary bed of next organ on in the circulatory system |
| proto-oncogenes | promote cell proliferation (most regulate proliferation) and gain of function mutations in cancer |
| examples of proto-oncogenes | EGFR and Myc |
| tumour suppressor (TS) genes | inhibit events leading to cancer (most regulate proliferation, immortality & apoptosis) and loss of function mutations in cancer |
| difference between function changes of proto-oncogenes and TS genes during cancer | proto-oncogenes gain of function mutations in cancer (become oncogenes) and TS genes loss of function mutations in cancer |
| examples of tumour suppressor genes (TS) | p53 and Rb |
| examples of familial syndromes (3) | retinoblastoma, colon cancer, and breast cancer |
| translocation oncogene examples (2) | cytogenetics and Bcr-Abl |
| describe oncogene amplification | multiple copies of genes generated where tumours can contain 100-150 copies of some oncogenes eg MYC in neuroblastoma |
| explain familial retinoblastoma phenotype | appears to be dominant at level of whole organism but the phenotype of the mutant allele is recessive at cellular level (if dominant Rb+/Rb- so one RB tumour suppressor gene still works so need to be recessive Rb-/Rb- to get cancer) |
| explain LOH | loss of heterozygosity - when second mutation occurs by different mutational process with a higher frequency (eg mitotic recombination) leading to 2 mutant genes eg in Rb-/Rb- |
| which part of the cell cycle does p53 act | G1 + G2 phases |
| which part of the cell cycle does Rb act | G1 |
| order of the cell cycle | G1 -> S -> G2 -> M |
| how can oncogenes be formed (4) | deletion or point mutation in coding sequence, regulatory mutation, gene amplification, and chromosome rearrangement |
| chromosomal translocation | pieces of 2 different chromosomes break off and switch places making a new abnormal gene |
| explain secondary tumours and their relationship with metastasis | cells move to the part of the body where the environment is most suitable, and tumour cells are larger and tend to get stuck in capillary bed of the next organ on in the circulatoy system |
Created by:
kablooey
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