Epigenetic Changes in Cancer
The study of how covalent marks on DNA and histones
are involved in the origin and spread of cancer cells
is also leading to new therapeutic strategies.
Much of the current hype in epigenetics stems from the recognition of its role in human cancer. Yet, intriguingly, the first epigenetic change in human tumors—global genomic DNA hypomethylation—was reported way back in the early 1980s, at about the same time the first genetic mutation in an oncogene was discovered.1 So why the delay in recognizing the importance of epigenetics in cancer?
In the 1980s epigenetics was a fledgling discipline, hampered by methodological limitations, while genetic knowledge of cancer was expanding exponentially. By the mid-1990s however, classical tumor suppressor genes, such as p16INK4a, hMLH1, and VHL,2 were shown to undergo a specific epigenetic hit (the inactivation of gene expression by CpG island hypermethylation), resulting in a major acceleration in the field. We now know that so-called “epigenetic changes” explain many hallmark features of malignant disease: these genes are deregulated not at the DNA level, but at the complexly packaged chromatin level, which ultimately results in cell dysfunction.
EPIGENETICS: “The inheritance of patterns of DNAand RNA activity that do not depend on the naked nucleotide sequence. By “inheritance,” we mean a memory of such activity transmitted from one cell generation to the next (through mitosis).”
Epigenetics may be important for the cancer field, but what does the term really mean? Truth be told, it has many definitions, which have changed over the years as our knowledge has changed. Researchers studying this discipline recognize how bewildering such a nebulous term can be to nonexperts, and they get together from time to time to put forward better explanations and nomenclatures, but they usually come up empty-handed, or with recommendations that people do not remember. Thus, we have to go back to the classics. Waddington defined epigenetics in 1939 as “the causal interactions between genes and their products, which bring the phenotype into being.” Adrian Bird redefined the term as “the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.” I prefer a more concrete definition: the inheritance of patterns of DNA and RNA activity that do not depend on the naked nucleotide sequence. By “inheritance,” we mean a memory of such activity transmitted from one cell generation to the next (through mitosis), or from one organismal generation to the next during meiosis. Meiotic inheritance is perhaps more provocative, as there is still scant direct evidence of epigenetic inheritance from one generation to the next, but genomic imprinting is a good example: when it goes awry it can lead to diseases such as Prader-Willi syndrome.
Cambridge Healthtech Institute
March 1, 2011
March 12, 2011
March 14, 2011
March 14, 2011