p16 Epimutation Causes Cancer
14 March 2015: Hypermethylation of the promoter region of p16 causes cancer and reduces survival in mice according to a recent report by Lanlan Shen and her colleagues in The Journal of Clinical Investigation.
The history of p16 as a human tumor suppressor gene is complex. Only months after gene deletion evidence from a variety of tumor cell lines indicated the involvement of p16 in the genesis of cancer (Nobori et al. 1994; Kamb et al. 1994), its tumor suppressor function was brought into question (Spruck et al. 1994; Cairns et al. 1994).
According to the two-hit theory of carcinogenesis by Knudson (Knudson 1971), a tumor suppressor is characterized by both copies of the gene being inactivated genetically, thereby eliminating its growth inhibition. Thus, tumors with loss of heterozygosity (LOH) at 9p21 - the chromosomal location of p16 - should have a high frequency of intragenic mutations in the other allele that block gene function. In contrast to this prediction, primary tumors with LOH at the p16 locus had a paucity of mutations in the remaining allele (Spruck et al. 1994; Cairns et al. 1994).
This conundrum appeared to be resolved in 1995 by the finding that p16 function is often inactivated in tumors by promoter hypermethylation (Merlo et al. 1995). Nevertheless, there has always been the nagging question: Does tumor hypermethylation at the p16 locus cause or result from cancer formation? This critically important question has now been answered twenty years later by an elegant set of experiments. By using a strategy to target DNA methylation directly to the p16 promoter in mice, epigenetic inactivation of p16 function has been demonstrated unequivocally to cause tumor formation (Yu et al. 2015).