Molecular Pathology of Tumours Flashcards
Identify the main properties of malignant cells.
- Disordered proliferation
- Disordered apoptosis
- Disordered differentiation
- Disordered relationship between proliferating cells and surrounding environment (invasion, metastasis, angiogenesis)
Describe the main different steps of cancer.
- Tissue is normal
- Dysplasia (some loss of stratification + immature cells escape from basal cell layer)
- Cancer in situ (total loss of stratification + immature cells throughout + BM intact)
- Invasion (Erosion of BM + tumour gains access to vascular channels)
- Metastasis (Cells escape from tumour via lymphatics or blood vessels)
Describe the concept of cancer clonality.
- A mutation gives one cell an advantage
- This cell survives and proliferates
- A second mutation increases the advantage
- The cell with double advantage survives and proliferates
- A third mutation further increases the advantage
However, most tumors are probably not strictly clonal; all cancer cells in a tumor seldom have the exact same set of mutations. Tumors tend to be subclonal, with all cancer cells having a single common ancestor (clonal) but with later evolution resulting in some mutations shared among all cancer cells but others restricted to sub-populations of cancer cells, which means not all cells in a tumour are genetically identical.
What sorts of genes are altered in tumour cells ?
- Oncogenes (activated)
2. Tumour-supressor-gene (inactivated)
Describe the process of activation of oncogenes.
- Normal cells have proto-oncogene
- Single mutation events in proto-oncogenes create the oncogene (because DOMINANT mutation (gain of function) so only need one copy of mutation to affect phenotype)
- Oncogene then drive neoplastic behavior in cells (abnormal proliferation which persists even after stimulus withdrawn)
-Different mechanisms:
1. DIRECT MUTATIONS in coding sequence of gene leading to hyperactive protein made in normal amounts. E.G. Gly12Val ras means that RAS remains active for longer. Hence cell can signal independently of growth factor (sending signals to cell telling it to divide)
2. GENE AMPLIFICATION: multiple copies of same gene, resulting in normal protein being present but overproduced.
E.G. Over expressed growth factors Her2 in breast cancer.
3. CHROMOSOMAL REARRANGEMENT:
Either a) Regulatory part of gene X against coding region for gene Y, resulting in abnormal expression of that rearranged gene product, and thus normal protein overproduction
Or b) Fusion to actively transcribed gene produces hyperactive fusion protein (part of protein X fused with part of protein Y)
E.G. Philadelphia chromosome in MCL.
What are the different functions of oncogenes ? Give an example of oncogen for each function and the cancer they cause.
- Growth Factor: Increased number (sis = PDGF in fibrosarcoma)
- Growth Factor Receptor: Increased number/activated (HER2 in breast cancer)
- Signal Transducer: Interfere with intracellular signaling (ras in colon cancer)
- Transcription Factor: Directly stimulate cell cycle dependent transcription (myc in Burkitt’s lymphoma)
Describe the process of activation of tumor supressor genes.
- 2 copies of tumour supressor gene.
- First mutation event inactivates the first tumour supressor gene copy (Phenotypically, no problem because RECESSIVE MUTATION (loss of function))
- Second mutation event inactivates the second tumour supressor gene copy.
- Two inactivating mutations functionally eliminate tumour supressor gene, stimulating cell survival and proliferation
Describe the main features of retinoblastoma.
- Eye tumour
- Affects children
- Can affect either one or two eyes
- 2/3 cases sporadic/unilateral (older onset 2.5-3 years)
- 1/3 bilateral (early onset 9 months)
- Majority of cases survive
Why does retinoblastoma affect some patients unilaterally and other bilaterally ?
Knudson’s two hit hypothesis:
- Both copies of RB1 gene disrupted in tumor.
- May arise in both copies of the gene in the same cell by chance (rare and sporadic) in which case unilateral retinoblastoma rises
- May arise because patient has inherited one defective copy of the gene already (affecting every cell of body). In this situation only need one further mutation to occur by chance and tumor will arise. Because each eye has already had one predisposing mutation (inherited one) bilateral retinoblastoma more likely.
Why does mutating Rb drive carcinogenesis ?
- RB normally inhibits proliferation, represses action of E2F, a transcription factor required to transcribe genes such as DNA polymerase required for entry into S phase.
- At certain point in cell cycle RB becomes inactivated by phosphorylation, repression is relieved and cells can move into S phase.
- In tumours RB is inactivated so there can be expression of S phase genes and cell driven towards proliferation even when it wouldn’t normally do so.
Describe the main possible functions of tumor repressor genes. Give a couple specific examples of genes for each function, as well as what occurs following their mutation.
1) GATEKEEPER
- Inhibit proliferation or stimulate death of cells, esp. those with DNA damage
- Sends negative signals to cell
2) CARETAKER
- Maintain integrity of genome by promoting DNA repair
- Repair can be through a) nucleotide excision repair b) Mismatch repair c) DNA double strand break repair
Give examples of gatekeeper and caretaker genes, as well as the resulting condition following their mutation.
GATEKEEPERS
- APC (Adenomatous polyposis coli) - Keeps level of transcription of genes required for proliferation very low. Mutated in FAP (Familial adenomatous polyposis) and about 80% of sporadic colon cancers.
- RB1 - mutated in Retinoblastoma
CARETAKERS
- Mutations in genes responsible for nucleotide excision repair lead to Xeroderma Pigmentosa (result in excision mis-formed bases eg following uv thymine dimers)
- Mutations in genes responsible for mismatch repair lead to Hereditary Non-Polyposis Colon Cancer
- BRCA1 or BRCA2(responsible for DNA DS break repair mechanism) mutation linked with breast and ovarian cancer
What is the function of p53 ? What happens when p53 is mutated ?
Both caretaker and gatekeeper
1)
-Senses damage to DNA
2)
-Stops cells from dividing (stops cell cycle) so DNA repair can occur
-Block angiogenesis
-If cell severely damaged, will also activate cell death pathways
Overall, activates genes whose products implement these effects.
Tumour formation will likely occur if p53 is mutated.
What is the Li-Fraumeni Syndrome ?
Inherited familial predisposition to a wide range of certain, often rare, cancers, due to a mutation in p53 tumor suppressor gene.
Describe the nature of P53 mutations.
- P53 is a transcription factor (ie binds DNA at particular sequences and activates transcription of genes with those sequences such as genes involved in controlling cell cycle or repair).
- 95% of mutations occur in central region (part that binds to specific sequences in DNA)
- Most mutations are missense mutations which cause loss of function and prevent DNA binding.
