Unanswered questions about the role of promoter methylation in carcinogenesis.

It has been proposed that tumor suppressor genes can be silenced by ectopic de novo methylation during tumor progression and that this epigenetic silencing is an alternative to mutation in tumor suppressor inactivation during oncogenic transformation. However, methylation may follow inactivation and may not directly participate in tumor progression. There are no genetic data that implicate ectopic de novo methylation in cancer, and no DNA methyltransferase gene has been shown to be mutated in any cancer. Promoter methylation at tumor suppressor loci may be a consequence of transcriptional inactivity imposed by mutations in upstream components of the transcriptional machinery or signal transduction pathways. Current estimates of the importance of epigenetic changes in the etiology of cancer may be inflated, and consequences may have been mistaken for causes in some cases.