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Epigenetic Determinants of Cancer Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Epigenetic Determinants of Cancer Stephen B. Baylin1 and Peter A. Jones2 1Cancer Biology Program, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21287; 2Van Andel Research Institute, Grand Rapids, Michigan 49503 Correspondence: [email protected] SUMMARY Epigenetic changes are present in all human cancers and are now known to cooperate with genetic alterations to drive the cancer phenotype. These changes involve DNA methylation, histone modifiers and readers, chromatin remodelers, microRNAs, and other components of chromatin. Cancer genetics and epigenetics are inextricably linked in generating the malignant phenotype; epigenetic changes can cause mutations in genes, and, conversely, mutations are frequently observed in genes that modify the epigenome. Epigenetic therapies, in which the goal is to reverse these changes, are now one standard of care for a preleukemic disorder and form of lymphoma. The application of epigenetic therapies in the treatment of solid tumors is also emerging as a viable therapeutic route. Outline 1 The biological basis of cancer 7 Summary of major research issues for understanding epigenetic gene silencing 2 The importance of chromatin in cancer to cancer 8 DNA methylation abnormalities 3 The role of DNA methylation as biomarkers for cancer in cancer detection and monitoring cancer prognosis 4 Hypermethylated gene promoters in cancer 9 Epigenetic therapy 5 The importance of epigenetic gene silencing References in early tumor progression 6 The molecular anatomy of epigenetically silenced cancer genes Editors: C. David Allis, Marie-Laure Caparros, Thomas Jenuwein, Danny Reinberg, and Monika Lachner Additional Perspectives on Epigenetics available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a019505 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a019505 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press S.B. Baylin and P.A. Jones OVERVIEW Cancer is caused by the somatically heritable deregulation of in the way histone-modifying enzymes function may occur. A genes that control the processes governing when cells divide, change in a protein’s ability to read histone marks, and hence die, and move from one part of the body to another. During bind to chromatin, or alterations in the way nucleosome-re- carcinogenesis, genes can become activated in such a way modeling or histone exchange complexes function can result. that enhances division or prevents cell death (oncogene). Al- Finally, changes in regulatory microRNA (miRNA) expression ternatively, genes can become inactivated so that they are no patterns have been noted. longer available to apply the brakes to these processes (tumor- This article focuses predominantly on how cancer is af- suppressor gene). It is the interplay between these two classes fected by this third pathway (i.e., epigenetic mechanisms). of genes that results in the formation of cancer. The basic molecular mechanisms responsible for maintaining Tumor-suppressor genes (TSGs) can become inactivated the silenced state are quite well understood, as outlined in this by at least three pathways: (1) through mutations, in which collection. Consequently, we also know that epigenetic si- their functions become disabled; (2) a gene can be completely lencing has profound implications for cancer prevention, de- lost and thus not be available to work appropriately (loss of tection, and therapies. We now have drugs approved by the heterozygosity); and (3) a gene can be switched off in a so- U.S. Food and Drug Administration (FDA) that are used to matically heritable fashion by epigenetic changes, rather than reverse epigenetic changes and restore gene activity to cancer by mutation of the DNA sequence. Epigenetic silencing can cells. Also, because changes in DNA methylation can be de- occur by deregulation of the epigenetic machinery at several tected with a high degree of sensitivity, many strategies are different levels; it may involve inappropriate methylation of able to detect cancer early by finding changes in DNA meth- cytosine (C) residues in CpG sequence motifs that reside with- ylation. The translational opportunities for epigenetics in hu- in control regions governing gene expression. Also, changes to man cancer research, detection, prevention, and treatment histone posttranslational modifications (PTMs) or aberrations are, therefore, quite extraordinary. 2 Cite this article as Cold Spring Harb Perspect Biol 2016;8:a019505 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Epigenetic Determinants of Cancer 1 THE BIOLOGICAL BASIS OF CANCER theepigeneticmachinerythatarenowknowntobeperturbed in cancer. These epigenomic changes not onlyare associated Cancer is ultimately a disease of gene expression in which with altered patterns of expression for otherwise wild-type the complex networks governing homeostasis in multicel- genes,but,insomecases,mayalsobecausaltotheirchanged lular organisms become deranged, allowing cells to grow expression state. The recognition of an epigenetic compo- without reference to the needs of the organism as a whole. nent in tumorigenesis, or the existence of a cancer “epige- Great advancements have been made in delineating the nome,”has led to new opportunities for the understanding, subset of cellular control pathways subject to derangement detection, treatment, and prevention of cancer. in human cancer (Table 1). The realization that distinct Signaling gene (oncogene) mutations in many human sets of cellular control pathways are affected and heritably cancers are often dominant and drive the formation of disabled in almost all cancers is a key concept that has cancers. An example would be ras, which when mutated, advanced the field (Hanahan and Weinberg 2011). Histor- enhances the activity of the gene product to stimulate ically, research has focused on the genetic basis of cancer, growth. Genetic mutations or epigenetic silencing of particularly, in terms of how mutational activation of on- TSGs, on the other hand, are often recessive, requiring dis- cogenes or inactivation of tumor-suppressor genes (TSGs) ruptive events in both allelic copies of a gene for the full underpins these above pathway changes. However, since the expression of the transformed phenotype. The idea that 1990s, a growing research endeavor has centered on the both copies of a TSG have to be incapacitated in a malignant recognition that heritable changes, regulated by epigenetic cell line was proposed by Knudson (2001) in his “two- or alterations, may also be critical for the evolution of all hu- multiple-hit” hypothesis and has found wide acceptance. It man cancer types (Baylin and Jones 2011). is now realized that three classes of “hits” can participate in Epigenetic alterations can be observed as abnormal pat- different combinations to cause a complete loss of activity terns of DNA methylation, disrupted patterns of histone of TSGs. Direct mutations in the coding sequence may posttranslational modifications (PTMs), and changes in occur, loss of parts or entire copies of genes, or epigenetic chromatincompositionand/ororganization.Changesinthe silencing, can cooperate with each other to result in the epigenome largely occur through disrupting the epigenetic disablement of key control genes. Another growing concept machinery, and Figure 1 illustrates the different elements of discussed in this article is that there is an intense coopera- tion between genetic and epigenetic abnormalities to drive Table 1. Examples of key cellular pathways disrupted in human can- cers by genetic and epigenetic mechanisms the initiation and progression of cancer (Fig. 1) (Baylin and Jones 2011; Youand Jones 2012; Garrawayand Lander 2013; Example of genetic Example of epigenetic Pathway alteration alteration Shen and Laird 2013). Most recently, excitement has cen- tered on the realization that most cancers actually harbor Self sufficiency in Mutations in Ras Methylation of frequent mutations in genes that encode for components of growth signals gene RASSFIA gene Insensitivity to Mutation in TGF-b Down-regulation of the epigenetic machinery, potentially resulting in abnor- antigrowth signals receptors TGF-b receptors malities in the epigenome, which may affect gene expres- Tissue invasion and Mutation in E- Methylation of E- sion patterns and genomic stability (Baylin and Jones 2011; metastasis cadherin gene cadherin promoter You and Jones 2012; Garraway and Lander 2013; Shen and Limitless replicative Mutation in p16 Silencing of p16 or pRb Laird 2013). Some of the growing list of genes frequently potential and pRb genes genes by promoter mutated in cancer, encoding proteins central to establishing methylation normal control of chromatin and DNA methylation pat- Sustained Silencing of angiogenesis thrombospondin-1 terns, are illustrated in Figure 1 and more exhaustively, list- Evading apoptosis Mutation in p53 Methylation of DAPK, ed in Table 2 or the Appendices of Audia and Campbell ASC/TMS1, and (2014) (Baylin and Jones 2011; You and Jones 2012; Garr- HIC1 away and Lander 2013; Shen and Laird 2013). Although DNA repair capacity Mutations in Methylation of GST Pi, most of the consequences of these mutations remain to be MLH1, MSH2 O6-MGMT,
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