The Epigenetics Revolution полностью

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.

The epigenetic frontier in cancer

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].