But cancer isn’t just a result of too much cell proliferation. If cells divide too quickly but are otherwise normal, they form structures called benign tumours. These may be unsightly and uncomfortable but unless they press on a vital organ and affect its activity, they are unlikely in themselves to be fatal. In full-blown cancer the cells don’t just divide too often, they are also abnormal and can start to invade other tissues.
A mole is a benign tumour. So is a little outgrowth in the inside of the large intestine, called a polyp. Neither a mole nor a polyp is dangerous in itself. The problem is that the more of these moles or polyps you have, the greater the likelihood that one of them will go the next step, and develop an abnormality that will take it further along the path towards full-blown cancer.
This implies something rather important, that has been demonstrated in a large number of studies. Cancer is not a one-off event. Cancer is a multi-step process, where each additional step takes a cell further along the road to becoming malignant. This is true even in cases where patients inherit a very strong pre-disposition to cancer. One example is pre-menopausal breast cancer, which runs in some families. Women who inherit a mutated copy of a gene called BRCA1 are at very high risk of early and aggressive breast cancer, which is difficult to treat effectively. But even these women aren’t born with active breast cancer. It takes many years before the cancer develops, because other defects have to accumulate as well.
So, cells accumulate defects as they move increasingly close to becoming cancerous. These defects must be transmitted from mother cell to daughter cell, because otherwise they would be lost each time a cell divided. These defects must be heritable as the cancer develops. Understandably, for a very long time, the attention of the scientific community focused on identifying mutations in the genes involved in the development of cancer. They were looking for alterations in the genetic code, the fundamental blueprint. They were particularly interested in the tumour suppressor genes as these are the genes that are usually mutated in the inherited cancer syndromes.
Humans tend to have two copies of each tumour suppressor gene, as most are carried on the autosomes. As a cell becomes increasingly cancerous, both copies of key tumour suppressor genes usually get switched off (inactivated). In many cases this may be because the gene has mutated in the cancer cells. This is known as somatic mutation – it has happened in body cells at some point during normal life. These are called somatic mutations to distinguish them from genetic mutations, the ones that are transmitted from parent to child. The mutations that inactivate the two copies of a tumour suppressor may be quite variable. In some cases there may be changes in the amino acid sequence, so that the gene can’t produce a functional protein any more. In other cases, there may be loss of the relevant part of the chromosome in the increasingly cancerous cells. In an individual patient, one copy of a specific tumour suppressor may carry a mutation that changes the amino acid sequence and the other may have suffered a micro-deletion.
It’s abundantly clear that these events do happen, and quite frequently, but often it’s been difficult to identify exactly how a tumour suppressor has mutated. In the last fifteen years, we’ve started to realise that there is another way that a tumour suppressor gene can become inactivated. The gene may be silenced epigenetically. If the DNA at the promoter becomes excessively methylated or the histones are covered in repressive modifications, the tumour suppressor will be switched off. The gene has been inactivated without changing the underlying blueprint.
Various labs have identified cancers where this has clearly happened. One of the first reports was in a type of kidney cancer called clear-cell renal carcinoma. A key step in the development of this kind of cancer is the inactivation of a specific tumour suppressor gene called VHL. In 1994, a group headed by the hugely influential Stephen Baylin from Johns Hopkins Medical Institution in Baltimore analysed the CpG island in front of the VHL gene. In 19 per cent of the clear-cell renal carcinoma samples that they analysed, the DNA of the island was hypermethylated. This switched off expression of this key tumour suppressor gene, and was almost certainly a major event in cancer progression in these individuals[180].
Promoter methylation was not restricted to the VHL tumour suppressor and renal cancer. Professor Baylin and colleagues subsequently analysed the BRCA1 tumour suppressor gene in breast cancer. They analysed cases where there was no family history of this disease, and the cancer wasn’t caused by the mutations in BRCA1 that we discussed a few paragraphs ago. In 13 per cent of these sporadic cases of breast cancer, the BRCA1 CpG island was hypermethylated[181]. Broader abnormal patterns of DNA methylation in cancer were reported by Jean-Pierre Issa from the MD Anderson Cancer Center in Houston, in collaboration with Stephen Baylin. Their collaborative work showed that over 20 per cent of colon cancers had high levels of promoter DNA methylation, at many different genes simultaneously[182].
Follow-on work showed that it’s not just DNA methylation that changes in cancer. There is also direct evidence for histone modifications leading to repression of tumour suppressor genes. For example, the histones associated with a tumour suppressor gene called ARHI had low levels of acetylation in breast cancer[183]. A similar relationship exists for the PER1 tumour suppressor in a form of lung cancer called non-small cell[184]. In both cases, there was a relationship between the levels of histone acetylation and the expression of the tumour suppressor – the lower the levels of acetylation, the lower the expression of the gene. Because these genes are both tumour suppressors, their decreased expression would mean that the cell would find it harder to put the brakes on proliferation.
This realisation – that tumour suppressor genes are often silenced by epigenetic mechanisms – has led to considerable excitement in the field, because this potentially creates a new way of treating cancer. If you can turn one or more tumour suppressor genes back on in cancer cells, there is a fighting chance of reining in the crazy proliferation rate of those cells. The runaway train may not run away quite so fast down the track.
When scientists thought that tumour suppressors were inactivated by mutations or deletions, we didn’t have many options for turning these genes back on. There are trials in progress to test if gene therapy can be used to achieve this. There may be circumstances where gene therapy will prove effective, but this is by no means certain. Gene therapy has struggled to deliver on the initial hopes for this technology, in all sorts of diseases. It can be very difficult to get the genes delivered into the right cells, and to get them to switch on when they are there. Even when we’re able to do this, we often find that the body gets rid of these extra genes, so any initial benefit is lost. There have also been relatively rare cases where the gene therapy itself has led to cancer, because it has had unexpected effects which have led to increased cell proliferation. The scientific community hasn’t given up hope for gene therapy and for some conditions it may yet prove to be the right approach[185]. But for diseases like cancer, where we would need to treat a lot of people, it’s expensive and difficult.
185
For a recent review of a disorder where gene therapy is proving broadly effective see Ferrua et al. (2010),