Qualified Promise: DNA Methylation Assays for the Detection and Classification of Human Cancers

In the last decade, epigenetic changes have been recognized as important factors in the development and progression of human cancers. Specifically, alterations of DNA methylation patterns are now thought to contribute to altered gene expression and chromosomal instability, to an often comparable degree as genetic alterations such as point mutations, insertions, deletions, chromosomal translocations, gains, and losses. Of note, DNA methylation patterns in cancer cells can change in both directions, that is, decreases as well as increases are found. Decreased methylation (“hypomethylation”) and increased methylation (“hypermethylation”) can occur independently of each other, but also simultaneously. While some methylation changes are subtle, two stand out as clearly pathological. The sequences surrounding the transcriptional start sites of many genes are particularly rich in the dinucleotide CpG compared to the rest of the genome. Many of these sequences, termed “CpG-islands,” are normally devoid of DNA methylation. Therefore, hypermethylation of such CpG-islands is evidently an aberrant process that is largely restricted to cancers. Limited and “patchy” CpG-island hypermethylation is observed in preneoplastic and aging tissues, while in some cancers, hundreds of CpG-islands become densely hypermethylated. Conversely, some sequences that are densely methylated in somatic cells become hypomethylated. In normal somatic cells, the CpG-rich satellite sequences SAT2 and SAT3 and interspersed CpG-rich retrotransposons like LINE-1 and ALU are strongly methylated. As these repeat sequences constitute the bulk of