Abstract
Although at the genetic level cancer is caused by diverse mutations, epigenetic modifications are characteristic of all cancers, from apparently normal precursor tissue to advanced metastatic disease, and these epigenetic modifications drive tumour cell heterogeneity. We propose a unifying model of cancer in which epigenetic dysregulation allows rapid selection for tumour cell survival at the expense of the host. Mechanisms involve both genetic mutations and epigenetic modifications that disrupt the function of genes that regulate the epigenome itself. Several exciting recent discoveries also point to a genome-scale disruption of the epigenome that involves large blocks of DNA hypomethylation, mutations of epigenetic modifier genes and alterations of heterochromatin in cancer (including large organized chromatin lysine modifications (LOCKs) and lamin-associated domains (LADs)), all of which increase epigenetic and gene expression plasticity. Our model suggests a new approach to cancer diagnosis and therapy that focuses on epigenetic dysregulation and has great potential for risk detection and chemoprevention.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Weinhouse, S. Isozymes in cancer. Cancer Res. 31, 1166–1167 (1971).
Shih, C. & Weinberg, R. A. Isolation of a transforming sequence from a human bladder carcinoma cell line. Cell 29, 161–169 (1982).
Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983).
Knudson, A. G. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
Greger, V., Passarge, E., Hopping, W., Messmer, E. & Horsthemke, B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum. Genet. 83, 155–158 (1989).
Sakai, T. et al. Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Amer. J. Hum. Genet. 48, 880–888 (1991).
Hansen, K. D. et al. Increased methylation variation in epigenetic domains across cancer types. Nature Genet. 43, 768–775 (2011).
Boveri, T. Concerning the Origin of Malignant Tumors (Williams and Wilkins, 1929).
Zink, D., Fischer, A. H. & Nickerson, J. A. Nuclear structure in cancer cells. Nature Rev. Cancer 4, 677–687 (2004).
Lever, E. & Sheer, D. The role of nuclear organization in cancer. J. Pathol. 220, 114–125 (2010).
Wen, B., Wu, H., Shinkai, Y., Irizarry, R. A. & Feinberg, A. P. Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells. Nature Genet. 41, 246–250 (2009).
Zullo, J. M. et al. DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell 149, 1474–1487 (2012).
Hu, S., Cheng, L. & Wen, B. Large chromatin domains in pluripotent and differentiated cells. Acta Biochim. Biophys. Sin. (Shanghai) 44, 48–53 (2012).
Peric-Hupkes, D. et al. Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. Mol. Cell 38, 603–613 (2010).
Reddy, K. L., Zullo, J. M., Bertolino, E. & Singh, H. Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 452, 243–247 (2008).
Chow, K. H., Factor, R. E. & Ullman, K. S. The nuclear envelope environment and its cancer connections. Nature Rev. Cancer 12, 196–209 (2012).
Hawkins, R. D. et al. Distinct epigenomic landscapes of pluripotent and lineage-committed human cells. Cell Stem Cell 6, 479–491 (2010).
Hon, G. C. et al. Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246–258 (2012).
McDonald, O. G., Wu, H., Timp, W., Doi, A. & Feinberg, A. P. Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nature Struct. Mol. Biol. 18, 867–874 (2011).
Zhou, V. W., Goren, A. & Bernstein, B. E. Charting histone modifications and the functional organization of mammalian genomes. Nature Rev. Genet. 12, 7–18 (2011).
Wen, B. et al. Euchromatin islands in large heterochromatin domains are enriched for CTCF binding and differentially DNA-methylated regions. BMC Genomics 13, 566 (2012).
Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nature Genet. 44, 40–46 (2012).
Ehrlich, M. DNA hypomethylation in cancer cells. Epigenomics 1, 239–259 (2009).
Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).
Lister, R. et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68–73 (2011).
De, S. & Michor, F. DNA secondary structures and epigenetic determinants of cancer genome evolution. Nature Struct. Mol. Biol. 18, 950–955 (2011).
Nestor, C., Ruzov, A., Meehan, R. & Dunican, D. Enzymatic approaches and bisulfite sequencing cannot distinguish between 5-methylcytosine and 5-hydroxymethylcytosine in DNA. Biotechniques 48, 317–319 (2010).
Jin, S.-G., Kadam, S. & Pfeifer, G. P. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res. 38, e125 (2010).
Chen, M.-L. et al. Quantification of 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from hepatocellular carcinoma tissues by capillary hydrophilic-interaction liquid chromatography/quadrupole TOF mass spectrometry. Clin. Chem. 59, 824–832 (2013).
Lian, Christine, G. et al. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell 150, 1135–1146 (2012).
Zhang, L.-T. et al. Quantification of the sixth DNA base 5-hydroxymethylcytosine in colorectal cancer tissue and C-26 cell line. Bioanalysis 5, 839–845 (2013).
Booth, M. J. et al. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336, 934–937 (2012).
Sun, Z. et al. High-resolution enzymatic mapping of genomic 5-hydroxymethylcytosine in mouse embryonic stem cells. Cell Rep. 3, 567–576 (2013).
Wolf, S. F. & Migeon, B. R. Studies of X chromosome DNA methylation in normal human cells. Nature 295, 667–671 (1982).
Bird, A., Taggart, M., Frommer, M., Miller, O. J. & Macleod, D. A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA. Cell 40, 91–99 (1985).
Goelz, S. E., Vogelstein, B., Hamilton, S. R. & Feinberg, A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228, 187–190 (1985).
Feinberg, A. P., Gehrke, C. W., Kuo, K. C. & Ehrlich, M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 48, 1159–1161 (1988).
Feinberg, A. P. & Vogelstein, B. Hypomethylation of ras oncogenes in primary human cancers. Biochem. Biophys. Res. Commun. 111, 47–54 (1983).
De Smet, C. et al. The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation. Proc. Natl Acad. Sci. USA 93, 7149–7153 (1996).
Iacobuzio-Donahue, C. A. et al. Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Amer. J. Pathol. 162, 1151–1162 (2003).
Oshimo, Y. et al. Promoter methylation of cyclin D2 gene in gastric carcinoma. Int. J. Oncol. 23, 1663–1670 (2003).
Akiyama, Y., Maesawa, C., Ogasawara, S., Terashima, M. & Masuda, T. Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Am. J. Pathol. 163, 1911–1919 (2003).
Cho, M. et al. Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma. Br. J. Cancer 85, 563–567 (2001).
Nakamura, N. & Takenaga, K. Hypomethylation of the metastasis-associated S100A4 gene correlates with gene activation in human colon adenocarcinoma cell lines. Clin. Exper. Metastasis 16, 471–479 (1998).
Badal, V. et al. CpG methylation of human papillomavirus type 16 DNA in cervical cancer cell lines and in clinical specimens: genomic hypomethylation correlates with carcinogenic progression. J. Virol. 77, 6227–6234 (2003).
de Capoa, A. et al. DNA demethylation is directly related to tumour progression: evidence in normal, pre-malignant and malignant cells from uterine cervix samples. Oncol. Rep. 10, 545–549 (2003).
Sato, N. et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 63, 4158–4166 (2003).
Piyathilake, C. J. et al. Race- and age-dependent alterations in global methylation of DNA in squamous cell carcinoma of the lung (United States). Cancer Causes Control 14, 37–42 (2003).
Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nature Rev. Cancer 11, 726–734 (2011).
Jones, P. A. et al. De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc. Natl Acad. Sci. USA 87, 6117–6121 (1990).
Bestor, T. H. Unanswered questions about the role of promoter methylation in carcinogenesis. Ann. NY Acad. Sci. 983, 22–27 (2003).
Hosoya, K. et al. Adenomatous polyposis coli 1A is likely to be methylated as a passenger in human gastric carcinogenesis. Cancer Lett. 285, 182–189 (2009).
Levanon, D. et al. Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function. EMBO Mol. Med. 3, 593–604 (2011).
Hitchins, M. P. et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N. Engl. J. Med. 356, 697–705 (2007).
Hitchins, M. P. & Ward, R. L. Erasure of MLH1 methylation in spermatozoa-implications for epigenetic inheritance. Nature Genet. 39, 1289 (2007).
Bachman, K. E. et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89–95 (2003).
Sproul, D. et al. Transcriptionally repressed genes become aberrantly methylated and distinguish tumors of different lineages in breast cancer. Proc. Natl Acad. Sci. USA 108, 4364–4369 (2011).
Sproul, D. et al. Tissue of origin determines cancer-associated CpG island promoter hypermethylation patterns. Genome Biol. 13, R84 (2012).
Irizarry, R. A. et al. Comprehensive high-throughput arrays for relative methylation (CHARM). Genome Res. 18, 780–790 (2008).
Irizarry, R. A. et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genet. 41, 178–186 (2009).
Doi, A. et al. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nature Genet. 41, 1350–1353 (2009).
Teschendorff, A. et al. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 4, 24 (2012).
Corrada Bravo, H., Pihur, V., McCall, M., Irizarry, R. & Leek, J. Gene expression anti-profiles as a basis for accurate universal cancer signatures. BMC Bioinformatics 13, 272 (2012).
Wang, G. G., Allis, C. D. & Chi, P. Chromatin remodeling and cancer, part II: ATP-dependent chromatin remodeling. Trends Mol. Med. 13, 373–380 (2007).
Wang, G. G., Allis, C. D. & Chi, P. Chromatin remodeling and cancer, part I: covalent histone modifications. Trends Mol. Med. 13, 363–372 (2007).
Roberts, C. W. & Orkin, S. H. The SWI/SNF complex--chromatin and cancer. Nature Rev. Cancer 4, 133–142 (2004).
Kaplan, N. et al. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458, 362–366 (2009).
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).
Mito, Y., Henikoff, J. G. & Henikoff, S. Genome-scale profiling of histone H3.3 replacement patterns. Nature Genet. 37, 1090–1097 (2005).
Zofall, M. et al. Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs. Nature 461, 419–422 (2009).
Gardner, K. E., Allis, C. D. & Strahl, B. D. Operating on chromatin, a colorful language where context matters. J. Mol. Biol. 409, 36–46 (2011).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Young, N. L. et al. High throughput characterization of combinatorial histone codes. Mol. Cell. Proteomics 8, 2266–2284 (2009).
Voigt, P. et al. Asymmetrically modified nucleosomes. Cell 151, 181–193 (2012).
Ohm, J. E. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genet. 39, 237–242 (2007).
Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nature Genet. 39, 157–158 (2007).
Chodavarapu, R. K. et al. Relationship between nucleosome positioning and DNA methylation. Nature 466, 388–392 (2010).
Gupta, R. A. et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076 (2010).
Yu, W. et al. Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202–206 (2008).
Guil, S. & Esteller, M. Cis-acting noncoding RNAs: friends and foes. Nature Struct. Mol. Biol. 19, 1068–1075 (2012).
Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).
Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).
Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011).
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).
Krivtsov, A. V. & Armstrong, S. A. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev. Cancer 7, 823–833 (2007).
Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nature Genet. 43, 309–315 (2011).
Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Kosmider, O. et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica 94, 1676–1681 (2009).
Pasqualucci, L. et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature 471, 189–195 (2011).
Pasqualucci, L. et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nature Genet. 43, 830–837 (2011).
Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).
Mullighan, C. G. et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature 471, 235–239 (2011).
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genet. 44, 251–253 (2012).
Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).
Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).
Cooper, D. N., Mort, M., Stenson, P. D., Ball, E. V. & Chuzhanova, N. A. Methylation-mediated deamination of 5-methylcytosine appears to give rise to mutations causing human inherited disease in CpNpG trinucleotides, as well as in CpG dinucleotides. Hum. Genomics 4, 406–410 (2010).
Greenman, C. et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).
Schuster-Bockler, B. & Lehner, B. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature 488, 504–507 (2012).
Jiang, Y. et al. Common fragile sites are characterized by histone hypoacetylation. Hum. Mol. Genet. 18, 4501–4512 (2009).
Fudenberg, G., Getz, G., Meyerson, M. & Mirny, L. A. High order chromatin architecture shapes the landscape of chromosomal alterations in cancer. Nature Biotech. 29, 1109–1113 (2011).
Miremadi, A., Oestergaard, M. Z., Pharoah, P. D. & Caldas, C. Cancer genetics of epigenetic genes. Human Mol. Genet. 16 (Suppl. 1), R28–R49 (2007).
Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).
Iliopoulos, D., Hirsch, H. A. & Struhl, K. An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139, 693–706 (2009).
Yamanaka, S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10, 678–684 (2012).
Suvà, M. L., Riggi, N. & Bernstein, B. E. Epigenetic reprogramming in cancer. Science 339, 1567–1570 (2013).
Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38–51 (2006).
Waddington, C. H. The Strategy of the Genes: A Discussion of Some Aspects of Theoretical Biology (Allen & Unwin, 1957).
Raser, J. M. & O'Shea, E. K. Control of stochasticity in eukaryotic gene expression. Science 304, 1811–1814 (2004).
Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).
Rando, O. J. & Verstrepen, K. J. Timescales of genetic and epigenetic inheritance. Cell 128, 655–668 (2007).
Feinberg, A. P. & Irizarry, R. A. Evolution in health and medicine Sackler colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc. Natl Acad. Sci. USA 107 (Suppl. 1), 1757–1764 (2010).
Alvarez, H. et al. Widespread hypomethylation occurs early and synergizes with gene amplification during esophageal carcinogenesis. PLoS Genet. 7, e1001356 (2011).
Shah, M. Y. et al. DNMT3B7, a truncated DNMT3B isoform expressed in human tumors, disrupts embryonic development and accelerates lymphomagenesis. Cancer Res. 70, 5840–5850 (2010).
Lande, R. Natural selection and random genetic drift in phenotypic evolution. Evolution 30, 314–334 (1976).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Kaneda, A. & Feinberg, A. P. Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res. 65, 11236–11240 (2005).
Timp, W., Levchenko, A. & Feinberg, A. P. A new link between epigenetic progenitor lesions in cancer and the dynamics of signal transduction. Cell Cycle 8, 383–390 (2009).
Kondo, Y. & Issa, J. P. Epigenetic changes in colorectal cancer. Cancer Metastasis Rev. 23, 29–39 (2004).
Issa, J. P. Aging, DNA methylation and cancer. Crit. Rev. Oncol. Hematol. 32, 31–43 (1999).
Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013).
Cui, H. et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299, 1753–1755 (2003).
Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005).
Teschendorff, A. E. & Widschwendter, M. Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions. Bioinformatics 28, 1487–1494 (2012).
Siddique, H., Zou, J. P., Rao, V. N. & Reddy, E. The BRCA2 is a histone acetyltransferase. Oncogene 16, 2283 (1998).
Fuks, F., Milner, J. & Kouzarides, T. BRCA2 associates with acetyltransferase activity when bound to P/CAF. Oncogene 17, 2531 (1998).
Esteve, P. O., Chin, H. G. & Pradhan, S. Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc. Natl Acad. Sci. USA 102, 1000–1005 (2005).
Zhu, P. et al. Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. Cancer Cell 5, 455–463 (2004).
Campbell, P. M. & Szyf, M. Human DNA methyltransferase gene DNMT1 is regulated by the APC pathway. Carcinogenesis 24, 17–24 (2003).
Sun, L. et al. Phosphatidylinositol 3-kinase/protein kinase B pathway stabilizes DNA methyltransferase I protein and maintains DNA methylation. Cell. Signal. 19, 2255–2263 (2007).
Lofton-Day, C. et al. DNA methylation biomarkers for blood-based colorectal cancer screening. Clin. Chem. 54, 414–423 (2008).
Warren, J. D. et al. Septin 9 methylated DNA is a sensitive and specific blood test for colorectal cancer. BMC Med. 9, 133 (2011).
Zou, H. et al. Highly methylated genes in colorectal neoplasia: implications for screening. Cancer Epidemiol. Biomarkers Prev. 16, 2686–2696 (2007).
Lee, W. H. et al. Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. Proc. Natl Acad. Sci. USA 91, 11733–11737 (1994).
Zhuang, J. et al. The dynamics and prognostic potential of DNA methylation changes at stem cell gene loci in women's cancer. PLoS Genet. 8, e1002517 (2012).
Li, M. et al. Sensitive digital quantification of DNA methylation in clinical samples. Nature Biotech. 27, 858–863 (2009).
Silber, J. R., Bobola, M. S., Blank, A. & Chamberlain, M. C. O6-Methylguanine-DNA methyltransferase in glioma therapy: promise and problems. Biochim. Biophys. Acta 1826, 71–82 (2012).
Rodriguez-Paredes, M. & Esteller, M. Cancer epigenetics reaches mainstream oncology. Nature Med. 17, 330–339 (2011).
Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem. Biol. 8, 890–896 (2012).
Fiskus, W. et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 114, 2733–2743 (2009).
Popovici-Muller, J. et al. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med. Chem. Lett. 3, 850–855 (2012).
Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).
Hull, M. A. Nutritional agents with anti-inflammatory properties in chemoprevention of colorectal neoplasia. Recent Results Cancer Res. 191, 143–156 (2013).
Kraus, S., Naumov, I. & Arber, N. COX-2 active agents in the chemoprevention of colorectal cancer. Recent Results Cancer Res. 191, 95–103 (2013).
Joshi, P. H. et al. A point-by-point response to recent arguments against the use of statins in primary prevention: this statement is endorsed by the American Society for Preventive Cardiology. Clin. Cardiol. 35, 404–409 (2012).
Yuasa, Y. et al. Insulin-like growth factor 2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk. Int. J. Cancer 131, 2596–2603 (2012).
Kaneda, A. et al. Enhanced sensitivity to IGF-II signaling links loss of imprinting of IGF2 to increased cell proliferation and tumor risk. Proc. Natl Acad. Sci. USA 104, 20926–20931 (2007).
Sjoblom, T. et al. The consensus coding sequences of human breast and colorectal cancers. Science 314, 268–274 (2006).
Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).
Kanai, Y., Ushijima, S., Nakanishi, Y., Sakamoto, M. & Hirohashi, S. Mutation of the DNA methyltransferase (DNMT) 1 gene in human colorectal cancers. Cancer Lett. 192, 75–82 (2003).
Tefferi, A. et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 23, 905–911 (2009).
Langemeijer, S. M. et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nature Genet. 41, 838–842 (2009).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. New Engl. J. Med. 360, 765–773 (2009).
Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).
Gui, Y. et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nature Genet. 43, 875–878 (2011).
Ward, R., Johnson, M., Shridhar, V., van Deursen, J. & Couch, F. J. CBP truncating mutations in ovarian cancer. J. Med. Genet. 42, 514–518 (2005).
Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).
Kishimoto, M. et al. Mutations and deletions of the CBP gene in human lung cancer. Clin. Cancer Res. 11, 512–519 (2005).
Berger, M. F. et al. The genomic complexity of primary human prostate cancer. Nature 470, 214–220 (2011).
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
Cromer, M. K. et al. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J. Clin. Endocrinol. Metab. 97, E1774–E1781 (2012).
Pugh, T. J. et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488, 106–110 (2012).
Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011).
Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet. 42, 181–185 (2010).
Ernst, T. et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genet. 42, 722–726 (2010).
Bodor, C. et al. EZH2 Y641 mutations in follicular lymphoma. Leukemia 25, 726–729 (2011).
Guichard, C. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nature Genet. 44, 694–698 (2012).
Network, T. C.G. A. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).
Hodis, E. et al. A landscape of driver mutations in melanoma. Cell 150, 251–263 (2012).
Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).
Biegel, J. A. et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).
Woodson, K. et al. Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women. J. Natl Cancer Inst. 96, 407–410 (2004).
Yun, K., Soejima, H., Merrie, A. E. H., McCall, J. L. & Reeve, A. E. Analysis of IGF2 gene imprinting in breast and colorectal cancer by allele specific-PCR. J. Pathol. 187, 518–522 (1999).
Nakagawa, M. et al. Expression profile of class I histone deacetylases in human cancer tissues. Oncol. Rep. 18, 769–774 (2007).
Choi, J. H. et al. Expression profile of histone deacetylase 1 in gastric cancer tissues. Jpn J. Cancer Res. 92, 1300–1304 (2001).
Halkidou, K. et al. Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 59, 177–189 (2004).
Kawai, H., Li, H., Avraham, S., Jiang, S. & Avraham, H. K. Overexpression of histone deacetylase HDAC1 modulates breast cancer progression by negative regulation of estrogen receptor alpha. Int. J. Cancer 107, 353–358 (2003).
Lin, Z. et al. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin. Cancer Res. 15, 570–577 (2009).
Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).
Ozdag, H. et al. Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics 7, 90 (2006).
Huang, B. H. et al. Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1. Cell Death Differ. 12, 395–404 (2005).
Wilson, A. J. et al. Histone deacetylase 3 (HDAC3) and other class I HDACs regulate colon cell maturation and p21 expression and are deregulated in human colon cancer. J. Biol. Chem. 281, 13548–13558 (2006).
Zhang, Z. et al. HDAC6 expression is correlated with better survival in breast cancer. Clin. Cancer Res. 10, 6962–6968 (2004).
Jung-Hynes, B., Nihal, M., Zhong, W. & Ahmad, N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J. Biol. Chem. 284, 3823–3832 (2009).
Ashraf, N. et al. Altered sirtuin expression is associated with node-positive breast cancer. Br. J. Cancer 95, 1056–1061 (2006).
Lu, P. J. et al. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J. Biol. Chem. 274, 15633–15645 (1999).
Silva, F. P. et al. Enhanced methyltransferase activity of SMYD3 by the cleavage of its N-terminal region in human cancer cells. Oncogene 27, 2686–2692 (2008).
Northcott, P. A. et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nature Genet. 41, 465–472 (2009).
Peng, D. F. et al. DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas. Carcinogenesis 27, 1160–1168 (2006).
Saito, Y. et al. Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int. J. Cancer 105, 527–532 (2003).
Nakagawa, T. et al. DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis. J. Urol. 173, 1767–1771 (2005).
Agoston, A. T. et al. Increased protein stability causes DNA methyltransferase 1 dysregulation in breast cancer. J. Biol. Chem. 280, 18302–18310 (2005).
Butcher, D. T. & Rodenhiser, D. I. Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours. Eur. J. Cancer 43, 210–219 (2007).
McCarthy, H. et al. High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor-prognosis chronic lymphocytic leukemia. Blood 101, 4903–4908 (2003).
Acknowledgements
This work was supported by US National Institute of Health (NIH) grants CA05438 and HG03233 to A.P.F. The authors thank D. Singer, I. Ernberg and J. Bradner for helpful discussions.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- Bivalent modifications
-
Nucleosomes containing both euchromatic histone H3 lysine 4 trimethylation (H3K4me3) and heterochromatic H3K27me3 post-translational modifications.
- Cancer hallmarks
-
Ten biological properties of cancer that are said to define the disease; we argue that they arise by natural selection for cellular survival at the expense of the host in the setting of epigenetic dysregulation and random variation.
- Cancer-specific differentially methylated regions
-
(cDMRs). Differentially methylated regions that distinguish cancer cells from normal cells.
- Chemoprevention
-
Administration of pharmacological compounds to reduce cancer incidence without certain knowledge of its effect on a given patient.
- CpG islands
-
(CGIs). Areas of high CpG dinucleotide density in the genome, typically defined as a region at least 200 bp long with >50% GC dinucleotides and an observed-to-expected CpG ratio of >0.6.
- CpG island shores
-
(CGI shores). The region 2 kb on either side of a CpG island, and the location of most cancer-specific, tissue-specific and reprogramming-specific differentially methylated regions.
- Epigenetic dysregulation
-
The loss of normal control of DNA methylation or chromatin as a result of injury, epigenetic change or mutation, leading to phenotypic drift.
- Epigenetic variability
-
Increased inter-sample variation in the methylation or chromatin state. This was recently identified as a common property of cancer, allowing for more accurate detection between samples.
- Euchromatin
-
Areas of the genome that are more open to transcription owing to post-translational modifications of histones and with less nucleosome density.
- Heterochromatin
-
Areas of the genome that are less open to transcription owing to post-translational modifications of histones and with greater nucleosome density. Facultative heterochromatin can change between the two states. Large organized chromatin lysine modifications and lamina-associated domains describe heterochromatin over relatively large regions and are associated with the nuclear membrane.
- Hypomethylated blocks
-
Large (mean 144 kb) regions that are broadly hypomethylated in cancer and that mostly overlap with large organized chromatin lysine modifications and lamina-associated domains.
- Lamina-associated domains
-
(LADs). Genomic regions located in the nuclear periphery that are associated with lamina (an inner nuclear membrane-associated protein) and usually have low expression levels.
- Large organized chromatin lysine modifications
-
(LOCKs). Large heterochromatic regions characterized by low gene expression that are altered between somatic and stem cells; they are typically lost in cancer cells.
- Loss of imprinting
-
(LOI). Loss of parent of origin-specific expression in cancer of imprinted genes, first observed for insulin-like growth factor 2 (IGF2) in Wilms' tumour and colorectal cancer.
- Ornstein–Uhlenbeck process
-
An overdamped Brownian harmonic oscillator — that is, stochastic variation from a normal state with no persistence of the rate of change — opposed by a stronger restoring force towards the equilibrium point. We are using this to model stochastic change in DNA methylation.
- Reprogramming-specific differentially methylated regions
-
(rDMRs). Differentially methylated regions that distinguish reprogrammed stem cells from somatic cells.
- Tissue-specific differentially methylated regions
-
(tDMRs). Differentially methylated regions that distinguish normal tissues from each other.
Rights and permissions
About this article
Cite this article
Timp, W., Feinberg, A. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nat Rev Cancer 13, 497–510 (2013). https://doi.org/10.1038/nrc3486
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc3486
This article is cited by
-
The role of H3K27me3 methylation in cancer development
Genome Instability & Disease (2024)
-
Low-dose arecoline regulates distinct core signaling pathways in oral submucous fibrosis and oral squamous cell carcinoma
BMC Oral Health (2023)
-
EZH2 in hepatocellular carcinoma: progression, immunity, and potential targeting therapies
Experimental Hematology & Oncology (2023)
-
KDM4C silencing inhibits cell migration and enhances radiosensitivity by inducing CXCL2 transcription in hepatocellular carcinoma
Cell Death Discovery (2023)
-
The role of the mitochondrial ribosomal protein family in detecting hepatocellular carcinoma and predicting prognosis, immune features, and drug sensitivity
Clinical and Translational Oncology (2023)
