Inherited tumour suppressor mutations and the two-hit hypothesis
Tumour suppressor genes (brakes on cell division) usually need both copies lost, so an inherited faulty copy is the first hit and one further hit is needed.
Remember
One hit is inherited and one is acquired: an inherited faulty tumour suppressor copy is the first hit, so only one more acquired hit is needed.
Memory aid
Think brakes versus accelerator: both brakes must fail, but an accelerator stuck on needs only one fault.
Use it to recall that tumour suppressor genes act like brakes, which usually need both copies lost, whereas an accelerator stuck on needs only one fault.
Each gene comes as two copies, called alleles, one from each parent. A tumour suppressor gene normally acts as a brake on cell division, and one working copy can still keep that brake on. Both alleles usually have to be inactivated before a tumour can grow.
This is Knudson's two-hit hypothesis. If one copy is inherited as mutated, that is the first hit, and the other copy can still protect the cell. When the second copy is mutated as well, that is the second hit: the cell is no longer protected, and the chance of a tumour growing is very high.
A germline mutation is a variation within the DNA of the egg or sperm, so it can be passed on and is present in every cell of the body. A somatic mutation is acquired later, in a single cell.
Retinoblastoma is a cancer of the retina, the light-sensing layer found at the back of the eye. In the inherited form, the child receives a mutation in one copy of the RB1 gene. Each retinal cell in both eyes then sits one hit away from losing its brake, so one further hit in any one cell is enough to start a tumour. That explains the early onset, with both eyes often affected. The inherited form is autosomal dominant (one faulty copy, on a chromosome that is not a sex chromosome, is enough to pass it on), but the tumour itself still needs the second hit.
APC is a tumour suppressor gene too, and its inherited mutation causes familial adenomatous polyposis (FAP): numerous polyps, which are small growths on the bowel lining, develop, and they turn into bowel cancer if untreated. A colon cell then needs only one more chance hit, in the healthy copy that remains.
Key facts
- Two-hit rule
- both copies (alleles) of a tumour suppressor gene usually have to be inactivated before a tumour grows.
- First hit
- an inherited faulty copy is present from birth, so only one more acquired hit is needed.
- Germline versus somatic
- a germline mutation is inherited and present from birth, while a somatic mutation is acquired later in a single cell.
- Age of onset
- retinoblastoma usually presents before the age of five, and one review found a mean age at diagnosis of 15 months for bilateral disease and 24 months for unilateral disease.
- Inheritance pattern
- inherited retinoblastoma is autosomal dominant, yet the tumour itself still needs the second hit.
- Oncogene contrast
- a proto-oncogene (a normal growth-promoting gene) becomes an oncogene when mutated, and one activating mutation (one that adds a function) can be enough.
Exam traps
- Losing a single copy of a tumour suppressor gene does not usually remove the brake, because the remaining copy can still protect the cell.
- Inherited retinoblastoma is autosomal dominant, not recessive: passing on one faulty copy is enough, and a later somatic mutation in a retinal cell removes the other copy rather than both copies arriving at conception.
- BRCA1 and BRCA2 are tumour suppressor genes too, but their inherited defects principally raise the risk of breast and ovarian cancers, so they do not explain retinoblastoma, which follows RB1 inactivation.
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