In the early 1980s, the cancer field was abuzz with the first discoveries of oncogenic mutations linked to cancer. The genetic mutation responsible for the transforming properties of the RAS oncogenes was found in 1982, to great acclaim (see Milestone 17). In this climate, the first observations of epigenetic abnormalities in cancer were overshadowed and ignored by many in the field. However, studies in the 1980s showed that epigenetic changes can occur to both oncogenes and tumour suppressors, and have led to our present appreciation of epigenetic markers as diagnostics and therapeutic targets for cancer.

Epigenetic phenomena can be defined as heritable changes in cellular information other than the DNA sequence, which usually involve covalent modifications to DNA or histones. These modifications are involved in controlling gene expression — for example, the methylation of DNA at CpG dinucleotides in gene promoters is associated with the silencing of transcription. In 1983, Andrew Feinberg and Bert Vogelstein purified DNA from several primary human tumour tissues and, using methylation-sensitive restriction enzymes, found lowered DNA methylation of specific genes compared with DNA from adjacent normal cells. With the predominant concept at the time being that cancer is caused by activation of oncogenes, these findings implied that altered DNA methylation could underlie oncogene activation.

Later in the 1980s, the concept of tumour-suppressor genes, such as retinoblastoma, was becoming well defined (see Milestone 11). So, it was encouraging when relevant epigenetic changes were found in these tumour-suppressor genes. For example, Valerie Greger et al. showed that an unmethylated CpG island at the 5′ end of the retinoblastoma gene becomes hypermethylated in tumours from retinoblastoma patients, leading the authors to speculate that methylation could contribute directly to the silencing of tumour suppressors. Later studies — such as those of Naoko Ohtani-Fujita et al. and James Herman et al. — correlated the methylation of the tumour-suppressor genes with their actual silencing in cancer.

More direct evidence linking DNA hypermethylation with cancer formation came several years later from Rudolf Jaenisch's group. They used mice carrying a 'Min' mutation in the adenomatous polyposis coli ( Apc ) gene. These mice develop intestinal polyps early in life and are a model system for the early stages of human colorectal cancer. Peter Laird et al. reduced DNA methylation in Min mice by mutating a DNA methyltransferase gene and using the methyltransferase inhibitor azacytidine. The reduced DNA methylation led to a decreased number of polyps in the animals, lending support to the idea that tumour-suppressor genes are hypermethylated and silenced in cancer, and can be reactivated by inhibiting DNA methylation.

DNA methylation inhibitors, such as azacytidine, are now approved for clinical use, although there is controversy about whether they work by reactivating tumour suppressors. Furthermore, the debate over whether altered DNA methylation has a causal role in initiating cancer remains alive today. Yet, it is remarkable that work carried out back in 1980 by Peter Jones and Shirley Taylor showing the effects of chemicals such as azacytidine on DNA methylation and cell differentiation, which attracted little attention at the time, opened the door to the idea of cancer treatment aimed at reversing DNA methylation.