Promoter hypermethylation—can this change alone ever designate true tumor suppressor gene function

We recently commented on the burgeoning evidence that epigenetically mediated gene silencing can selectively produce loss of key gene functions in cancer (1). In this issue of the Journal, Burbee et al. (2) report that yet another gene, RASSF1A, is silenced in association with promoter hypermeth-ylation in small-cell lung cancer (SCLC), in non-small-cell lung cancer (NSCLC), and in breast cancers. Dammann et al. (3) recently made a similar finding in lung tumors. Burbee et al. (2) demonstrate that the frequency of RASSF1A gene silencing vir-tually parallels that of the incidence of the loss of heterozygosity (LOH) for chromosome 3p21, the region that harbors the gene. Both groups (2,3) find that RASSF1A promoter hypermethyl-ation is an extremely frequent occurrence in SCLC, a tumor in which chromosome 3p LOH is almost always present and may be a seminal event for this disease (2,4). In both studies (2,3)