Do both TSG and Proto-oncogenes have to suffer mutations to cause cancer?

Question

I'm having a conceptual nightmare trying to understand when a group of cells may become cancerous and the more resources I consult the more confused I seem to get.

In order for a cell to become cancerous, does it have to mutate to knock out tumour suppressor genes and have a proto-oncogene become an oncogene?

I'm currently working on the basis that that is the case, or at least that a mutated TSG on its own will not cause uncontrolled division. However wikipedia seems to suggest that an oncogene alone can cause uncontrolled division with a functional TSG in place.

It could be a flaw in the idea I have that tumour suppressor genes only trigger apoptosis once a cell has started to divide rapidly, are they actually carrying it out to a regular schedule independent of oncogene presence?

Answer 1

There is a nice nature paper by Dr. Micheal Stratton et al. that I think might be a good place to start.

I think answering you question is complex, because different cancers will actually have different mechanisms that trigger their onset and aggressiveness and as such some have more complex mutational landscapes than others.

A good question to ask yourself is : what is a driver mutation and what is a passenger mutation. A driver mutation is usually what is driving the cancer, and it can be a proto-oncogene or TSG. Passenger mutations don't really have as much of an impact and result from the destructive tendencies of the driver mutations.

Answer 2

The typical idea is that several "hits" are required. The difference between proto-oncogene and TSG is mainly in their heritability - TSG mutations are usually recessive (because a heterozygote will still express sufficient suppressor, e.g. p53) whereas proto-oncogenes are dominant (if a consitutively active agent e.g. Ras is present, it doesn't matter if the other allele is under normal control).

A single "hit" in this way (TSG or proto-oncogene) may just cause the cell to die, which isn't a bad thing (in fact, TSG such as p53 often work by inducing apoptosis because proliferative errors make them accumulute). A tumour only results when a single cell accumulates sufficient mutations and genomic damage to gain a reproductive advantage over the cells in its vicinity.

The three defects a tumour cell needs to accumulate (at least according to our lectures) are usually unregulated proliferation, independence of growth factors (i.e. its milieu) and malfunctions in attachment proteins.

I'll gather references and a few example genes tomorrow, I remember all of those being in my lectures. For now, if you look at the BCR-ABL hybrid in chronic myeloid leukaemia that might give you an idea; there should be a lot of material on that available.