43.3 Genetic Basis of Malignancy Flashcards
(33 cards)
What are viral oncogenes?
cancer-inducing genes within oncogenic viruses
What are cellular proto-oncogenes?
Genes with normal roles in the regulation of cell growth, death or differentiation, but which contribute to malignancy as oncogenes when mutated, or inappropriately over-expressed.
*often GoF
What do oncogenes predispose the cell to?
Dysregulated proliferation –> malignancy/ tumorigenesis
What do oncogenes mostly encode?
- Transcription factors
- Factors in pro-growth signalling pathways (like mitogens and their receptors)
- Factors that enhance cell survival
What are proto-oncogenes?
NORMAL genes that can be mutated or overexpressed, then become oncogenes
Due to the single cell of origin, tumours are known as…
monoclonal
Since tumours are so rare, which events increases the likelihood of them forming?
- Predisposing events like UV radiation and smoking - increased mutation frequency
- A cell with a single mutation surviving, creating a cell lineage that acquires further mutations
- Accumulation over time of several independent mutations
Why are tumours rare?
- Mutations are rare - occur in 1 out of 106 mitotic cycles
- There are many repair mechanisms incl. 3’-5’ proofreading
- If mutations still persist - apoptotic and regulatory systems usually cause cell death
What is the evidence for the thought that usually many mutations occur before cells become cancerous?
The incidence rates for cancer overall climb as age increases
More time to accumulate mutations
*requirement for the accumulation of several independent genetic events.
What are the main types of carcinogens?
- Physical
- Chemical
What are examples of physical carcinogens?
UV and ionising radiation
What are examples of chemical carcinogens?
- Asbestos
- Tobacco smoke
- Alcohol
- Arsenic
How does malignancy develop?
Through cells in the body accumulating changes to their genes. E.g. activation of oncogenes, and loss of tumour suppressor genes.
What are the 2 different theories surrounding tumour heterogeneity?
Clonal evolution and cancer stem cell theory
What is the clonal evolution theory?
*Peter Nowell (1976) → tumours arise from single mutated cell –clonal expansion→ form clones –genetic instability→ accumulation of additional stochastic mutations as tumour progresses → (epi)genetic changes gives rise to distinct subpopulations.
*Heterogeneity allows for selection of subclones/populations w/ accumulated driver mutations
- Hence evolutionary advantage.
What is the cancer stem cell theory?
*Only CSCs (small subset of tumour cells that can self-renew + differentiate into non-tumorigenic progeny) are tumorigenic.
- I.e. can initiate + maintain tumour growth.
*Suggested heterogeneity develops over time as CSCs divide + differentiate asymmetrically → different tumour cell types w/ different phenotypes.
- Hence CSCs are source of heterogeneity
How can loss of heterozygosity occur?
- Chromosomal deletions or breaks that delete the tumour suppressor gene
- Somatic recombination during mitosis where the normal gene copy is replaced with a mutant copy - daughter cells have LOH
Since tumours are so rare, which events increases the likelihood of them forming?
- Predisposing events like UV radiation and smoking - increased mutation frequency
- A cell with a single mutation surviving, creating a cell lineage that acquires further mutations
- Accumulation over time of several independent mutations
What is an important area of research that has confirmed the importance of cancer genes and led to new identifications?
Cancer genome projects, using high-throughput gene sequencing
What is the role of tumour suppressor genes?
Encode proteins which suppress inappropriate cell cycle progression e.g. when DNA damage is present, by initiating cell cycle arrest, DNA repair, and apoptosis accordingly
What is the 2-hit hypothesis?
Knudson’s 2-hit hypothesis (1950s) → study of familial bilateral retinoblastoma.
Found degree of inheritance. Contrasted to unilateral retinoblastoma which didn’t show heritability.
Led Knudson to propose 2 hit hypothesis (AR inheritance):
1st hit = inherited mutation in TSG
2nd hit = somatic loss of heterozygosity.
Carriers predisposed to much ↑er lifetime risk.
What is the range of proteins that tumour suppressor genes encode?
*Gatekeeper genes
*Caretaker genes
*Landscaper genes
What are gatekeeper genes?
*Gatekeeper genes → direct regulation of cell growth.
*Through inhibition of cell cycle progression/ inducing apoptosis
*RB1 (gatekeeper) mutation
- Found in familial (bilateral) retinoblastoma + diverse variety of sporadic cancers.
What are caretaker genes?
maintain genome stability. If affected, allow mutations to accumulate.
