Cancer epigenetics in clinical practice

Cancer development is driven by the accumulation of alterations affecting the structure and function of the genome. Whereas genetic changes disrupt the DNA sequence, epigenetic alterations contribute to the acquisition of hallmark tumor capabilities by regulating gene expression programs that promote tumorigenesis. Shifts in DNA methylation and histone mark patterns, the two main epigenetic modifications, orchestrate tumor progression and metastasis. These cancer-specific events have been exploited as useful tools for diagnosis, monitoring, and treatment choice to aid clinical decision making. Moreover, the reversibility of epigenetic modifications, in contrast to the irreversibility of genetic changes, has made the epigenetic machinery an attractive target for drug development. This review summarizes the most advanced applications of epigenetic biomarkers and epigenetic drugs in the clinical setting, highlighting commercially available DNA methylation-based assays and epigenetic drugs already approved by the US Food and Drug Administration.     

Cancer epigenetics is no Mickey Mouse

Epigenetic changes are the most common alterations in human cancer, but it has been difficult to sort out cause and effect from studies of human tumors. Several recent nonlethal mouse models implicate both hypomethylation and loss of imprinting (LOI) in tumor formation, including a paper in this issue of Cancer Cell showing that transient hypomethylation in ES cells causes LOI and liver and intestinal tumors (). Hypomethylation appears to be a critical determinant of cancer, affecting chromosomal stability and specific gene targets.     

Cancer epigenetics in solid organ tumours: A primer for surgical oncologists

Cancer is initiated through both genetic and epigenetic alterations. The end-effect of such changes to the DNA machinery is a set of uncontrolled mechanisms of cell division, invasion and, eventually, metastasis. Epigenetic changes are now increasingly appreciated as an essential driver to the cancer phenotype. The epigenetic regulation of cancer is complex and not yet fully understood, but application of epigenetics to clinical practice and in cancer research has the potential to improve cancer care. Epigenetics changes do not cause changes in the DNA base-pairs (and, hence, does not alter the genetic code per se) but rather occur through methylation of DNA, by histone modifications, and, through changes to chromatin structure to alter genetic expression. Epigenetic regulators are characterized as writers, readers or erasers by their mechanisms of action. The human epigenome is influenced from cradle to grave, with internal and external life-time exposure influencing the epigenetic marks that may act as modifiers or drivers of carcinogenesis. Preventive and public health strategies may follow from better understanding of the life-time influence of the epigenome. Epigenetics may be used to define risk, to investigate mechanisms of carcinogenesis, to identify biomarkers, and to identify novel therapeutic options. Epigenetic alterations are found across many solid cancers and are increasingly making clinical impact to cancer management. Novel epigenetic drugs may be used for a more tailored and specific response to treatment of cancers. We present a primer on epigenetics for surgical oncologists with examples from colorectal cancer, breast cancer, pancreatic cancer and hepatocellular carcinoma.     

Cancer epigenetics and the potential of epigenetic drugs for treating solid tumors

Introduction: Epigenetic modification without DNA sequence mutation plays an important role in cancer development. Some small molecular inhibitors targeting key epigenetic molecules have been approved by the Food and Drug Administration to treat hematological malignancies. However, the anticancer effects of these drugs on solid tumors are not satisfactory, and the mechanisms of action remain largely unknown.

Areas covered: The review summarizes the latest research on cancer epigenetics and discusses the potentials and limitations of using epigenetic drugs to treat solid tumors. An analysis of possible reasons for epigenetic drug treatment failure in solid tumors in some clinical trials is discussed along with prospects for future development.

Expert commentary: Next-generation small molecule inhibitors will target novel epigenetic regulators with high cancer specificity. Combined modalities exploiting epigenetic drugs with chemo-/radiotherapy, molecular-targeting drugs, and immunotherapy will be able to effectively treat solid tumors in the near future.     

Cancer epigenetics: a perspective on the role of DNA methylation in acquired endocrine resistance

Epigenetic mechanisms, including DNA methylation, are responsible for determining and maintaining cell fate, stably differentiating the various tissues in our bodies. Increasing evidence shows that DNA methylation plays a significant role in cancer, from the silencing of tumor suppressors to the activation of oncogenes and the promotion of metastasis. Recent studies also suggest a role for DNA methylation in drug resistance. This perspective article discusses how DNA methylation may contribute to the development of acquired endocrine resistance, with a focus on breast cancer. In addition, we discuss DNA methylome profiling and how recent developments in this field are shedding new light on the role of epigenetics in endocrine resistance. Hormone ablation is the therapy of choice for hormone-sensitive breast tumors, yet as many as 40% of patients inevitably relapse, and these hormone refractory tumors often have a poor prognosis. Epigenetic studies could provide DNA methylation biomarkers to predict and diagnose acquired resistance in response to treatment. Elucidation of epigenetic mechanisms may also lead to the development of new treatments that specifically target epigenetic abnormalities or vulnerabilities in cancer cells. Expectations must be tempered by the fact that epigenetic mechanisms of endocrine resistance remain poorly understood, and further study is required to better understand how altering epigenetic pathways with therapeutics can promote or inhibit endocrine resistance in different contexts. Going forward, DNA methylome profiling will become increasingly central to epigenetic research, heralding a network-based approach to epigenetics that promises to advance our understanding of the etiology of cancer in ways not previously possible.     

Cancer research in an era when epigenetics is no longer "epi"-challenges and opportunities

正When I was learning epigenetics 17 years ago at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins,this field was like a small spring bud growing in the windy storm of genetics/genomics.Now,epigenetics is booming like gold mining in the American West,and every cancer scientist intends to make a fortune from it.When epigenetics eventually becomes a mainstream,or even leading,research field in biomedicine     

Lung cancer epigenetics and genetics

Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.     

The epigenetics of cancer etiology

Epigenetic dysregulation is central to cancer development and progression. This dysregulation includes hypomethylation leading to oncogene activation and chromosomal instability, hypermethylation and tumor suppressor gene silencing, and chromatin modification acting directly, and cooperatively with methylation changes, to modify gene expression. In addition, disrupted genomic imprinting appears to contribute to colorectal cancer risk, and serves as a gatekeeper in Wilms tumor. A cancer predisposing disorder, Beckwith-Wiedemann syndrome, usually arises from epigenetic errors, solidifying the causal role of epigenetics in cancer. While cancer epigenetics has been reviewed extensively elsewhere, the main focus of this review will be to present the view that epigenetics and genetics are complementary in the area of cancer etiology, the focus of this volume. I propose a hypothesis in which epigenetic alterations contribute to tumor progression, but they also increase the probability that genetic changes, when they occur, will lead to cancer initiation. This hypothesis could contribute to a new understanding of the role of environmental carcinogens that may not be fully explained through a purely genetic view or by tests, such as bacterial mutation frequency, that ignore epigenetic factors.     

Diagnostic and therapeutic applications of epigenetics

Epigenetic abnormalities, such as aberrant methylation of CpG islands, are inherited over cell divisions, and play important roles in carcinogenesis. Aberrant methylation of CpG islands specific to tumor cells can be used as a marker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect aberrant methylation. Methylations of specific genes or methylation patterns of groups of genes were found to be associated with responses to chemotherapeutics and prognosis. Methylation in non-cancerous tissues is now attracting attention as a tumor risk marker, and is emerging as a target for cancer prevention. Epigenetic alterations are potentially reversible. The use of DNA demethylating agents has turned out to be effective for hematological malignancies, and is being tested in solid tumors. Histone deacetylase inhibitors and methods for gene-specific epigenetic modification are being developed. Application of epigenetics to cancer diagnostics and therapeutics, and possibly to cancer prevention, is coming into clinics.     

三阴性乳腺癌与表观遗传学研究现状

目的：探讨表观遗传修饰在三阴性乳腺癌（triplenegativebreastcancer,TNBC）检测、诊断和靶向治疗中的机制及作用。方法：应用PubMed、CNKI全文数据库及Google学术搜索等检索系统,以“乳腺癌或三阴性乳腺癌和表观遗传学或DNA甲基化”等为关键词,检索2003—01—2013-12的相关文献,共检索到英文文献1055爷,中文文献35条。纳入标准：1）TNBC癌诊断与治疗;2）表观遗传学修饰机制;3）表观遗传学对TNBC癌的意义。根据纳入标准,符合分析的文献47篇。结果：DNA甲基化、组蛋白修饰及miRNA调控在TNBC的发生、发展中扮演重要角色,通过表观遗传修饰与TNBC相关基础研究的总结,以及在已有的实验研究或临床研究的基础上进行理论推测,对TNBC的临床诊断、预后和治疗具有借鉴意义。结论：通过研究表观遗传学修饰改变在TNBC发生、发展中的作用,可为将来TNBC患者的临床治疗提供新思路。     

miRNAss 与前列腺癌－表观遗传学新进展

前列腺癌的研究已深入到肿瘤细胞的分子水平,和大多数肿瘤发展一样,前列腺癌的发生发展是一个涉及多基因的过程.在前列腺癌发展的过程中,mieroRNAs在基因转录后调控中的表达起着主导作用,原癌基因的形成和激活与抑癌基因的失活也起着重要的作用.现就miRNAss和前列腺癌的表观遗传学新进展予以综述.