0611 - Cancer Genetics Flashcards
Describe the basic genetic mechanism causing cancer.
DNA mutation in tumour suppressor genes or proto-oncogenes, which leads to uncontrolled cell growth and cancer formation; acquired mutations always involved in causing cancer; germline mutations involved in a small percentage of cases.
Describe the role of P53 in the development of cancer.
- P53 is a tumour suppressor gene; it is a master regulator of apoptosis and the cell cycle
- in normal cells, P53 is kept at low levels and is short-lived
- when there is DNA damage, oxidative stress, osmotic shock or oncogene dysregulation, P53 numbers increase to control the situation
→ initiates DNA repair before cell division
→ arrests cell cycle at G1 and S phases
→ initiates apoptosis of damaged cells that cannot be repaired - in cancer cells, P53 is inactivated, deleted or non-functional, and so no control of mutations, leading to cell death (most commonly) and uncontrolled division of DNA damage
Describe the role of RB1 in the development of cancer.
- retinoblastoma (RB1) is a tumour suppressor gene involved in controlling the cell cycle
- in normal cells, RB1 is unphosphorylated and halts cell proliferation by inhibiting DNA synthesis
- in cancer cells, RB1 is inactive, or phosphorylated, and unable to inhibit DNA synthesis, leading to uncontrolled initiation of DNA synthesis and cell proliferation
Identify parts of the cell cycle important for the regulation of cancer.
Cell cycle:
Succession of organised molecular events that give the ability to the cell to produce the exact copy; DNA replication and segregation of replicated chromosomes are the main events; G1, S and G2 phases represent the interphase of a proliferating cell and constitute the time lapse between two consecutive mitoses; the differentiated cells that do not proliferate enter in the so-called G0 phase, which is a steady state phase or resting phase.
G1 phase - DNA synthesis preparatory phase; cellular contents, excluding chromosomes, duplicated
S phase - DNA replication
G2 phase - mitotic preparatory phase; cell “double checks” duplicated chromosomes for error, making any needed repairs
M phase - mitosis
G0 - cell cycle arrest
Checkpoints in the cell cycle prevent entry into S or P phase (G1/S checkpoint, and G2/M checkpoint) until any DNA damage repaired; proteins that do the checking (e.g. P53) are key to the regulation of cancer, because if they are mutated the checkpoints may be bypassed, leading to uncontrolled cell proliferation.
Define and provide examples of the following terms: oncogene, proto-oncogene, tumour suppressor gene.
Proto-oncogene: normal gene that can undergo mutation to become an oncogene; e.g. ABL1
Oncogene: gene that has the ability to induce cancer; e.g. mutant ABL1
Tumour suppressor: gene that protects a cell from one step on the path to cancer; aka anti-oncogene; e.g. P53, RB1
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Describe the difference between a familial/inherited and somatic cancer.
Inherited gene mutations: passed from parent to child through egg or sperm; the mutations are in every cell in the body.
Acquired mutations: not present in egg or sperm; acquired at some point; more common than inherited; mutation occurs in one cell and then passed onto any new cells that are the offspring to that cell.
Describe the two-hit model of cancer development.
- the two-hit theory of cancer causation explains the early onset of hereditary cancers (e.g. retinoblastoma, familial breast cancer) at multiple sites in the body
- one germline copy of a damaged gene present in every cell in the body inherited, and whilst not enough to enable cancer to develop on its own, a second hit to the good copy in the gene pair could occur somatically and produce cancer
- predicts that the chances for a germline mutation carrier to get a second somatic mutation at any of multiple sites in his/her body cells was much greater than the chances for a non-carrier to get two hits in the same cell
