BRCA1 and E-Cadherin Promoter Hypermethylation and Gene Inactivation in Cancer—Association or Mechanism?

Extract

The abnormal properties of cancer cells are attributable to alterations in gene sequence and expression. The genes that are mutated in cancer can be grouped into two classes: proto-oncogenes and tumor suppressor genes. Proto-oncogenes are affected by gain-of-function mutations in cancer, generating oncogenic variant copies (or alleles) with increased or novel functions, while tumor suppressor genes are inactivated. Tumor suppressor genes were initially hypothesized to be inactivated in cancer cells as a result of genetic defects of both alleles (i.e., the Knudson two-hit hypothesis). Many studies have validated this concept, demonstrating localized mutations in both tumor suppressor gene alleles or a localized mutation in one allele coupled with a loss of heterozygosity (LOH) in the other allele. However, there is now evidence that epigenetic events, such as hypermethylation of cytosine–guanine (CpG) sites in regulatory regions (e.g., the promoter), may be a critical alternative mechanism of tumor suppressor gene inactivation, including von Hippel–Lindau inactivation in some clear-cell renal cancers, p16^INK4a inactivation in some lung and other cancers, and MLH1 inactivation in many sporadic colon cancers with microsatellite instability (1–3). Two reports (4,5) in this issue of the Journal provide additional data consistent with the view that hypermethylation of the promoter regions of certain tumor suppressor genes may play an important role in extinguishing gene expression in cancer. However, before accepting the conclusion that hypermethylation of tumor suppressor gene promoters is invariably the cause of gene inactivation, it is worth evaluating the data in the two reports a bit more critically.