T h e
new engl and journal
n engl j med
Molecular Origins of Cancer
Epigenetics in Cancer
Manel Esteller, M.D., Ph.D.
From the Cancer Epigenetics Laboratory,
Spanish National Cancer Research Center,
Madrid. Address reprint requests to Dr.
Esteller at the Cancer Epigenetics Labo-
ratory, Spanish National Cancer Research
Center, Melchor Fernandez Almagro 3,
28029 Madrid, Spain, or at mesteller@
N Engl J Med 2008;358:1148-59.
Copyright © 2008 Massachusetts Medical Society.
lassic genetics alone cannot explain the diversity of pheno-
types within a population. Nor does classic genetics explain how, despite their
identical DNA sequences, monozygotic twins
or cloned animals
different phenotypes and different susceptibilities to a disease. The concept of epi-
genetics offers a partial explanation of these phenomena. First introduced by C.H.
Waddington in 1939 to name “the causal interactions between genes and their prod-
ucts, which bring the phenotype into being,”
epigenetics was later defined as heri-
table changes in gene expression that are not due to any alteration in the DNA se-
The best-known epigenetic marker is DNA methylation. The initial finding of
global hypomethylation of DNA in human tumors
was soon followed by the identifi-
cation of hypermethylated tumor-suppressor genes,
and then, more recently, the
discovery of inactivation of microRNA (miRNA) genes by DNA methylation.
and other demonstrations of how epigenetic changes can modify gene expression have
led to human epigenome projects
and epigenetic therapies.
Moreover, we now
know that DNA methylation occurs in a complex chromatin network and is influ-
enced by the modifications in histone structure that are commonly disrupted in cancer
Epigenetic research uses powerful techniques for the study of DNA methylation,
such as sodium bisulfite modification associated with polymerase-chain-reaction pro-
Terms used in epigenetic research are defined in the Glossary. Compre-
hensive epigenomic techniques
have yielded preliminary descriptions of the epi-
genomes of human cancer cells.
This review summarizes new developments
concerning hypermethylation of the promoter regions of tumor-suppressor genes
and describes possible applications of epigenetics to the treatment of patients with
Epigenetic Features of a Normal Cell
DNA methylation has critical roles in the control of gene activity and the architecture
of the nucleus of the cell. In humans, DNA methylation occurs in cytosines that pre-
cede guanines; these are called dinucleotide CpGs.