We have had a series of posts (starting here) stimulated by a debate in BioEssays about whether one major idea about cancer, that it is due to somatic mutations (SMT), is correct, or whether a very different local-tissue-environment model (TOFT) explains the disease.
Given what it seems that we know, we should expect a spectrum of causation to apply, and we think that's what's been observed. Clearly cancer is a disease of clonal expansion of cells, typically descendants of a single transformed founder cell. The job of cells is to behave--express subsets of the genes in their genome--in ways that suit their local signaling (inter-cellular communication) environment. Gene expression is how this works, so clearly either mutant genes or mistaken interpretation of the environment, can trigger misbehavior.
First, the SMT, the idea that cancer is entirely due to somatic mutations, should be tempered, because it is manifestly clear that inherited mutations play a role, not just somatic mutations (that occur in body cells but were not inherited from the patient's parents). As an overall generalization, cancers show mutations in many genes, but some of these have been inherited. Typically those are mutations that are 'recessive': if you get one 'bad' copy from one parent, but a good copy from your other parent, you're generally OK, unless you inherit deficient variants at other genes. You get cancer if the good copy is somatically mutated in a cell, as well perhaps as other mutations in other genes or changes in the cellular environment. Such genes are known as 'antioncogenes' or tumor supressor genes, because on their own they don't cause--and might function to hold back--abnormal cell behavior. These are the main known genes in which inherited mutations lead to cancer. TP53, a gene that encodes the tumor-suppressor protein p53, is an example.
Oncogenes are those than can actively lead a cell astray, 'causing' cancer on their own (probably other factors have to be present as well). Mutations in these genes are rarely inherited, because the affected embryo doesn't make its 0th birthday. If you suffer a somatic mutation in one of these (probably also if the cell has variants in additional genes, or the cell environment is changed somehow), you get cancer.
In either case, SMT argues that somatic mutations must contribute because, after all, you are born normal which means your inherited genotype didn't prevent proper tissue differentiation when you were an embryo. Debate was about how many or what or what types of genes were mutated somatically before someone got cancer. The age and rate of onset (age-specific 'hazard' function) seemed to reflect the number of changes that were needed to transform a cell, the number of cells at risk, and their cell-division rate.
The type of cancer that started us off on the path to the discovery of these aspects of cancer was the rare cancer of the retina (light perceiving layer inside the eye), retinoblastoma, or RB. RB mainly occurs by birth or in early childhood. It's rare, but one of the most stunning and influential discoveries--a true rather than hyped 'breakthrough'--was made in the early '70s by Al Knudson. He observed that in sporadic RB only one eye was affected and usually with only one primary tumor. But in the rare instance of inherited RB, both eyes were often affected, and by multiple independent tumors.
The idea struck Knudson that if some gene caused the tumor, then if no mutant copies of this gene were inherited, it would be very unlikely that any given retinal cell would be so unlucky as to experience mutations in both copies of the gene: hence sporadic RB is rare and unsually unilateral. But if one bad copy were inherited, the fetus would only need to 'wait' for the other copy to be hit. In the millions of newly forming retinal cells, it was reasonably likely that one or even many such cells would indeed be hit by another mutation.
The fact that RB occurred at birth rather than decades later, along with this idea about causation, suggested that there really was only one gene that needed to go bad. By luck, a group involving Bob Ferrell, who was in Houston with Al Knudson (as was yours truly), discovered a chromosome change that was associated with RB in a family or two, and this led to the discovery of the gene, which was named RB1.
This opened many doors! Knudson is widely honored, though he should in our opinion have been awarded a Nobel prize for his very insightful work (and he's a very nice person to boot!). Anyway, to continue the story of the door he opened, soon other childhood tumors (esp. Wilm's tumor of the kidney) were found to have similar genetic epidemiology. Then others, notably Bert Vogelstein and Ken Kinzler at Johns Hopkins, developed tests to see how often this phenomenon of somatic loss of a good copy of a tumor-suppressor gene occurred in people who had inherited one bad copy. They found evidence that led to the discovery of other tumor suppressor genes, the most famous of which had to do with colon cancer (and the Tp53 gene that's involved in cell behavior).
Most tumors take decades to develop, even breast cancer in people inheriting mutations in BRCA genes (which is also in the suppressor category). And this knitted tissue environmental factors (such as exposure to things including menstrual cycling and lactation that stimulated breast cell division) with genetic factors. Each patient may have a unique set of many different mutations in other genes, some perhaps inherited others acquired somatically, and these were not terrible in themselves but carcinogenic in combination. The idea of 'waiting' for these events to occur is strengthened by the discovery that BRCA works in a mutation-repair pathway. So if you can't repair mutations, you're more likely to collect a bad set of them in some cell.
A generally consistent picture emerged, of complex, multifactorial genetic and histological processes that accounted for much of the epidemiology and genetics of cancer. There are many aspects of this picture that require particular study and explanation. It seemed that we had a pretty good understanding of the causal landscape, even if the specifics were complex or elusive.
But a new paper in Nature raises questions about even the simple RB model that are challenging to answer, in light of the above ideas. That will be in Part V of this series on the causation of this dreaded disease--and what it tells us about basic cell biology.
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