Site-specific DNA hypermethylation is frequently implicated as a cancer-causing mechanism, but what of genome-wide hypomethylation, which also occurs in many human tumours? Whether this is a cause or consequence of cancer has long been debated, but Rudolf Jaenisch and colleagues, reporting in the 18 April issue of Science, have now developed a mouse model to address this question.
They generated viable, but small, mice that were compound heterozygous for a hypomorphic allele and a null allele of Dnmt1 — the DNA methyltransferase that maintains DNA methylation. These mice expressed just 10% of wild-type levels of the protein, and Southern blot analysis following digestion with a methylation-sensitive restriction enzyme revealed that global methylation levels were decreased. Interestingly, 80% of the mice developed aggressive T-cell lymphomas at 4–8 months of age. These were shown to be monoclonal, which indicates that hypomethylation initiates cancer in a single cell that undergoes other events to become a malignant tumour.
So how might hypomethylation induce this lymphomagenesis? The authors proposed three possible mechanisms: induction of endogenous retroviral elements could insertionally activate proto-oncogenes; proto-oncogenes could be activated by epigenetic effects; or genomic instability might be induced.
The first possibility was ruled out as retroviral element activation was not observed. c-Myc had already been found to be overexpressed in most of the hypomethylation-induced T-cell lymphomas, but this locus was not rearranged in any of the 18 tumours tested. This was in contrast to Moloney murine leukaemia virus (MMLV)-induced tumours, in which 3 of 12 tumours had an insertional rearrangement in c-Myc. It was also thought unlikely that the mechanism could be epigenetic, as hypomethylation existed throughout development and c-Myc was expressed at normal levels in the thymuses of 2–4-week-old mice.
However, there was already evidence that hypomethylation affected genomic stability, and this was confirmed by carrying out array-based comparative genome hybridization. When hypomethylation-induced tumours were compared with MMLV-induced tumours, a significant increase in chomosome gains — particularly of chromosome 15, which contains c-Myc — was observed. Only 2 of 12 tumours did not have this change, and these also had lower levels of c-Myc.
So, it seems that hypomethylation can cause tumorigenesis through genomic instability. A report by the same group, also in Science, provides further support for this, as they show that hypomethylation promotes cancer in tumour-prone mice — due to heterozygosity of the tumour suppressors Nf1 and Trp53 — because it increases the rate of loss of heterozygosity. Perhaps we should reconsider the use of demethylating agents to treat cancer in light of these results.
References
ORIGINAL RESEARCH PAPER
Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003)
Eden, A. et al. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003)
FURTHER READING
Lengauer, C. Cancer: an unstable liaison. Science 300, 442–443 (2003)
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Greenwood, E. Less is more. Nat Rev Cancer 3, 392 (2003). https://doi.org/10.1038/nrc1103
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DOI: https://doi.org/10.1038/nrc1103