Cancer Genetics

Edited by: Eugene Russo A. Merlo, J.G. Herman, L. Mao, D.J. Lee, E. Gabrielson, P.C. Burger, S.B. Baylin, D. Sidransky, "5´ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers," Nature Medicine, 1:686-92, 1995. (Cited in more than 170 papers through June 1997) Comments by David Sidransky, Johns Hopkins University School of Medicine GAINING CREDIBILITY: David Sidransky's lab showed that methylation is an important mechanism of gene inactivation. Although the phenomenon of methylation has attracted the attention of cancer researchers for some time, scientists have only recently recognized its potential role in the progression of human cancers. Methylation knocks out gene function; methyl groups placed on CpG islands (relatively rare clusters of cytosine and guanine bases connected by a phosphorylation site) effectively prevent gene transcription. If a tumor suppressor gene is methylated, cancerous growth may result. According to David Sidransky, director of the division of head and neck cancer research at Johns Hopkins University School of Medicine, this paper was one of the first to demonstrate that methylation was not merely a byproduct of cancerous growth. Rather, the research, which focused on the commonly seen tumor suppressor gene p16, showed that methylation is a mode of gene inactivation, like point mutations and deletions. "The reason the paper has been cited so often," surmises Sidransky, "is that although methylation has been part of cancer and cancer genetics for at least 10 years, it was unclear whether it was an associated phenomenon or whether it was really important in the progression of cancers. What this paper really did is show that in a variety of tumor types where there wasn't a point mutation or deletion, we saw methylation. I think it placed methylation and lack of transcription of a gene as an important step in the progression of human cancers." Methylation's gene-crippling effects aren't all bad-they are, in fact, essential to human development. "Methylation has always been seen as important because that was one way the genes were regulated and turned off at the right time," explains Sidransky. "In cancer cells, though, a gene that should normally be turned on is turned off by this methylation process. So it's just like a point mutation or deletion; it's just another way of knocking out the function of the gene. "Researchers have identified a whole variety of tumor-suppressor genes," he reports. "Now they're starting to look at methylation as an important mechanism of inactivation. So I think that for cancer genetics in general, the concept of methylation is firmly in place as a major player, rather than just a side issue, in the progression of human cancers." Sidransky's team focused on the well-known tumor suppressor gene p16 to demonstrate that methylation is by no means a rare phenomenon. He explains that "p16 was a very common target, and now it was combined with a very novel or less frequently seen method of inactivation." In fact, p16 is an important enough target to prompt the research team to carry out further studies. "In one of our current papers," Sidransky notes, "we say that p16, if you combine it with all methods of inactivation, is probably the most frequently altered gene in human cancer." He believes that the gene is probably more frequently altered than p53, the tumor suppressor gene commonly thought to be the most frequently affected by mechanisms like point mutation and deletion. Sidransky contends that the methylation process requires further study. It's still unclear exactly why methylation takes place-whether it's triggered by cancerous cells or whether a malfunctioning cell triggers methylation, which in turn causes cancerous growth. "We don't know if it's the cause of what's going on, or a consequence of what's going on in the cell," he says. "We don't understand the mechanism of how it happens-we only know the consequences once it's methylated."

Cancer Genetics

The Scientist Staff

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