Biochemistry

Edited by: Paul Smaglik J.G. Herman, A. Merlo, L. Mao, R.G. Lapidus, J.J. Issa, N.E. Davidson, D. Sidransky, S.B. Baylin, "Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers," Cancer Research, 55:4525-30, 1995. (Cited in more than 145 publications through October 1997) Comments by James G. Herman and Stephen B. Baylin, Johns Hopkins University Oncology Center During the high-profile days of genome building and gene sequencing, cancer researchers often identified genes with specific functions as if they were biological on/off switches. However, scientists now are finding that the mechanisms may be more complicated. Biochemistry's role in the activation or inactivation of genes has emerged from the shadows of mutations, as scientists are beginning to discern that both processes share important roles in causing cancer. ANOTHER MECHANISM: Johns Hopkins' James Herman says aberrant methylation can lead to the loss of the p16 gene's tumor suppressor function. Several years ago, investigators reported that in many human cancer types, especially in cultured cells, both copies of the tumor suppressor gene CDKN2/p16/MTS1 are deleted from the genome. Cells require protein from this gene to halt division at the proper times. Lacking the tumor suppressor allows cells to divide out of control. "Subsequent studies of noncultured tumors did not find as high a frequency of such 'homozygous' gene deletions, and the more common mechanism for disruption of tumor suppressor gene function-point mutations in the protein coding portion of the gene-were very infrequent," says James G. Herman, a researcher in the Oncology Center at the Johns Hopkins University School of Medicine. Controversy then arose concerning the true frequency and importance of p16 gene loss in human cancer. COMMON GENE: Since p16 is a common gene linked to cancer, its abnormal methylation could cause cancer, explains Johns Hopkins' Stephen Baylin. Herman and his colleagues searched for other mechanisms by which p16 gene function might be lost. They examined multiple tumor types and discovered that the process of aberrant DNA methylation of the starting regulatory portion of the p16 gene often was associated with the gene's inactivation. Methyl groups are added to DNA just after it is synthesized and maintained in the genome. The starting regions of the p16 gene, as is true of many genes, is not methylated in normal cells-and when methylated in the tumor cells, the gene loses the capacity to manufacture mRNA. "Our findings provided evidence that important tumor suppressor gene functions could be lost from cancer in ways other than protein coding region mutations," states Herman. "The frequency that the p16 gene is lost via deletions vs. abnormal methylation varies with tumor type, though we don't yet know why." Colon cancer has been especially interesting, he says, since loss of p16 gene function would not have been suspected in this tumor type from genetic analyses alone. Deletions or point mutations of this gene essentially are not found, even in cell cultures. However, the researchers found abnormal methylation of the gene frequently in both cultured and noncultured colon cancer cells. Stephen B. Baylin, also at the Hopkins Oncology Center, thinks the research has garnered attention, in part, because the p16 gene's function disappears in many types of human cancer. Previously, scientists attributed the disappearance to mutation. This paper offers another explanation. "From these studies, people now realize that for a complete search to determine if the function of a gene is truly lost from given tumor types, DNA methylation as well as mutations often needs to be considered," Baylin says. Future studies of abnormal DNA methylation in cancer will focus on continuing to define the genes involved and understanding why the aberrant methylation occurs. "We do not yet understand the precise causes, and these could be important to adding to our knowledge about different etiologies of specific tumor types and what makes tumors progress once the process has started," Baylin adds. "Since DNA methylation, unlike mutations, is a potentially reversible process, the study of this abnormality in cancer could have ramifications for developing new prevention and/or treatment strategies." Detection of the abnormally methylated DNA regions may provide new markers for early cancer diagnosis and risk assessment. Much of Herman's recent work has involved developing such procedures.

Biochemistry

The Scientist Staff

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