A decade of exploring the cancer epigenome — biological and translational implications

Baylin, Stephen B.; Jones, Peter A.

doi:10.1038/nrc3130

Cited by 2,481 publications

(2,193 citation statements)

References 159 publications

(204 reference statements)

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“…The past decade has witnessed an explosion of knowledge about the epigenetic regulatory changes that occur in cancer cells, leading to the concept that cancer is also a disease of the “epigenome” (Baylin and Jones, 2011). Specific changes in histone acetylation and methylation patterns are being observed in various cancer types.…”

Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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It is a time of great promise and expectation for the applications of knowledge about mechanisms of cancer toward more effective and enduring therapies for human disease. Conceptualizations such as the hallmarks of cancer are providing an organizing principle with which to distill and rationalize the abject complexities of cancer phenotypes and genotypes across the spectrum of the human disease. A countervailing reality, however, involves the variable and often transitory responses to most mechanism‐based targeted therapies, returning full circle to the complexity, arguing that the unique biology and genetics of a patient's tumor will in the future necessarily need to be incorporated into the decisions about optimal treatment strategies, the frontier of personalized cancer medicine. This perspective highlights considerations, metrics, and methods that may prove instrumental in charting the landscape of evaluating individual tumors so to better inform diagnosis, prognosis, and therapy. Integral to the consideration is remarkable heterogeneity and variability, evidently embedded in cancer cells, but likely also in the cell types composing the supportive and interactive stroma of the tumor microenvironment (e.g., leukocytes and fibroblasts), whose diversity in form, regulation, function, and abundance may prove to rival that of the cancer cells themselves. By comprehensively interrogating both parenchyma and stroma of patients' cancers with a suite of parametric tools, the promise of mechanism‐based therapy may truly be realized.

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Section: Addressing Tumor Heterogeneity and Complexitymentioning

confidence: 99%

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

2012

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“…In this review, we outline the dynamics of DNA methylation over the lifespan and define two distinct phenomena that collectively contribute to these changes. We focus only on healthy aging; for excellent reviews of the epigenetics of age‐associated disease including cancer, please see Baylin & Jones (2011), Bergman & Cedar (2013), and Teschendorff et al . (2013).…”

Section: Introductionmentioning

confidence: 99%

DNA methylation and healthy human aging

2015

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SummaryThe process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next‐generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site‐specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age‐related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining ‘epigenetic age’ for human health and outline some important caveats to existing and future studies.

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“…However, it is becoming increasingly clear that the impact of epigenetics on both the tumor cell and the tumor microenvironment plays a critical role in the development of drug resistance 9, 10, 11. Consistent with this hypothesis, previous laboratory and clinical data suggest that an epigenetic strategy may overcome chemotherapy resistance and mediate a return to a baseline state of treatment susceptibility in various cancers 11, 12, 13, 14, 15. Epigenetic perturbations, particularly hypomethylating agents (HMA), re‐sensitize cancer cells to chemotherapy presumably by resetting the epigenetic infrastructure and altering gene expression in the tumor 16, 17, 18.…”

Section: Introductionmentioning

confidence: 99%

“…The concentration required to reverse tumor‐specific DNA methylation is much lower than that needed to produce maximal cytotoxicity 18, 19, 20. The apparent reversibility of resistance by epigenetic interference has the potential to turn the arrow of time backwards, replacing progression with regression, and thus provides a good rational for the use of low‐dose decitabine as an antidote to the resistance to current standard chemotherapies and as a blueprint to significantly extend patient survival 11, 16, 17…”

Section: Introductionmentioning

confidence: 99%

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

Chen

Nie

Liu

et al. 2018

Intl Journal of Cancer

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The pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment. The potential re‐sensitivity property to chemo‐ and immunotherapy of low‐dose decitabine has been evident both preclinically and in previous phase I trials. We conducted a phase Ib/II trial evaluating low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers. Forty‐five patients received either the 5‐day decitabine treatment with subsequent readministration of the previously resistant chemotherapy (decitabine‐primed chemotherapy, D‐C cohort) or the aforementioned regimen followed by cytokine‐induced killer cells therapy (D‐C and cytokine‐induced killer [CIK] cell treatment, D‐C + CIK cohort) based on their treatment history. Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4%) of 45 patients. All AEs were controllable, and no patient experienced a treatment‐related death. The objective response rate (ORR) and disease control rate (DCR) were 24.44% and 82.22%, respectively, including two patients who achieved durable complete responses. Clinical response could be associated with treatment‐free interval and initial surgical resection history. ORR and DCR reached 28% and 92%, respectively, in the D‐C + CIK cohort. Consistently, the progression‐free survival (PFS) of the D‐C + CIK cohort compared favorably to the best PFS of the pre‐resistant unprimed therapy (p = 0.0001). The toxicity and ORRs exhibited were non‐significantly different between cancer types and treatment cohort. The safety and efficacy of decitabine‐primed re‐sensitization to chemoimmunotherapy is attractive and promising. These data warrant further large‐scale evaluation of drug‐resistant R/R AT cancer patients with advanced stage disease.

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A decade of exploring the cancer epigenome — biological and translational implications

Cited by 2,481 publications

References 159 publications

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

DNA methylation and healthy human aging

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

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