The promise and failures of epigenetic therapies for cancer treatment

Genetic mutations and gross structural defects in the DNA sequence permanently alter genetic loci in ways that significantly disrupt gene function. In sharp contrast, genes modified by aberrant epigenetic modifications remain structurally intact and are subject to partial or complete reversal of modifications that restore the original (i.e. non-diseased) state. Such reversibility makes epigenetic modifications ideal targets for therapeutic intervention. The epigenome of cancer cells is extensively modified by specific hypermethylation of the promoters of tumor suppressor genes relative to the extensive hypomethylation of repetitive sequences, overall loss of acetylation, and loss of repressive marks at microsatellite/repeat regions. In this review, we discuss emerging therapies targeting specific epigenetic modifications or epigenetic modifying enzymes either alone or in combination with other treatment regimens. The limitations posed by cancer treatments elicit unintended epigenetic modifications that result in exacerbation of tumor progression are also discussed. Lastly, a brief discussion of the specificity restrictions posed by epigenetic therapies and ways to address such limitations is presented.     

表观遗传学在结直肠癌中的应用进展

结直肠癌（CRC）的发生、发展伴随着许多基因的表达变化,但其具体调控机制至今仍未完全阐明。近年来对CRC表观遗传学尤其是微小RNA（miRNA）、异常DNA甲基化及组蛋白修饰状态等方面的研究受到广泛关注。研究证实,CRC进展过程中均存在异常的甲基化基因和miRNA的表达变化。与癌症基因组的基因突变一样,这类遗传学的分子改变在CRC中扮演着重要角色。表观遗传学的特异性改变可作为CRC诊断、治疗和预后的临床生物学标记物,对表观遗传学进行深入研究对CRC的防治具有重要指导意义。     

组蛋白去乙酰化酶及其抑制剂与结直肠癌的关系

组蛋白乙酰化、去乙酰化修饰影响到染色质重塑,在基因表达的表观遗传调控中扮演重要角色。结直肠癌是临床上最常见的恶性肿瘤之一,是我国第二高发的肿瘤,研究证实结直肠癌的发生发展与组蛋白去乙酰化酶（ｈｉｓｔｏｎｅ ｄｅａｃｅｔｙｌａｓｅｓ,ＨＤＡＣｓ）异常密切相关,ＨＤＡＣ抑制剂（ＨＤＡＣｉｎｈｉｂｉｔｏｒ,ＨＤＡＣｉ）靶向ＨＤＡＣｓ,大量研究已证实ＨＤＡＣｉ单用或联合其他药物对结直肠癌细胞具有诱导分化、促进凋亡等作用,并能提高结直肠癌细胞对化疗药物的敏感性,提示ＨＤＡＣ靶向治疗结直肠癌可能是今后又一个新的发展方向。     

Gastric cancer: An epigenetic view

Gastric cancer (GC) poses a serious threat worldwide with unfavorable prognosis mainly due to late diagnosis and limited therapies. Therefore, precise molecular classification and search for potential targets are required for diagnosis and treatment, as GC is complicated and heterogeneous in nature. Accumulating evidence indicates that epigenetics plays a vital role in gastric carcinogenesis and progression, including histone modifications, DNA methylation and non-coding RNAs. Epigenetic biomarkers and drugs are currently under intensive evaluations to ensure efficient clinical utility in GC. In this review, key epigenetic alterations and related functions and mechanisms are summarized in GC. We focus on integration of existing epigenetic findings in GC for the bench-to-bedside translation of some pivotal epigenetic alterations into clinical practice and also describe the vacant field waiting for investigation.     

Molecular approach to genetic and epigenetic pathogenesis of early-onset colorectal cancer

Colorectal cancer (CRC) is the third most frequent cancer type and the incidence of this disease is increasing gradually per year in individuals younger than 50 years old. The current knowledge is that early-onset CRC (EOCRC) cases are heterogeneous population that includes both hereditary and sporadic forms of the CRC. Although EOCRC cases have some distinguishing clinical and pathological features than elder age CRC, the molecular mechanism underlying the EOCRC is poorly clarified. Given the significance of CRC in the world of medicine, the present review will focus on the recent knowledge in the molecular basis of genetic and epigenetic mechanism of the hereditary forms of EOCRC, which includes Lynch syndrome, Familial CRC type X, Familial adenomatous polyposis, MutYH-associated polyposis, Juvenile polyposis syndrome, Peutz-Jeghers Syndrome and sporadic forms of EOCRC. Recent findings about molecular genetics and epigenetic basis of EOCRC gave rise to new alternative therapy protocols. Although exact diagnosis of these cases still remains complicated, the present review paves way for better predictions and contributes to more accurate diagnostic and therapeutic strategies into clinical approach.     

Leukocyte DNA methylation and colorectal cancer among male smokers

AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study. METHODS: About 221 incident CRC cases, and 219controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Il-lumina GoldenGate Methylation Cancer Panel I in prediagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression. RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P<0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a Pvalue of 1.0×10-4 . The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression. CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.     

大肠癌表观遗传修饰在东西方人口中的异同研究

大肠癌对全世界人口的危害仍尤为重大,在其研究领域,大肠癌表观遗传学的研究越来越受到研究者重视。从大肠癌表观遗传学中的DNA甲基化和组蛋白修饰两个主要方面,对比分析了东西方人口中大肠癌患者之间存在的异同。接着,初步介绍了东西方大肠癌患者用作生物标识和治疗靶点的表观遗传修饰基因的异同点。分析表明,虽然大肠癌在世界范围内有一些共同的特征,但其在不同人种中确实存在某些明显的表观遗传的不同,例如特异性基因甲基化以及组蛋白修饰位点和甲基化,乙酰化的程度不同在各国的研究中都已得到证实,这就为不同人种中大肠癌特异性的诊断、治疗及预后提供了依据。在进一步的规范研究方法和增加样本量的情况下,相信更多的大肠癌组织特异性的分子靶点将会被发现,继而针对单个患者的个体化治疗将有望实现。     

Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation

The original theory of the multi-step process of colorectal cancer (CRC), suggesting that the disease resulted from the accumulation of mutations in oncogenes and tumor suppressor genes in colonic mucosa cells, has been largely revised following the observation that epigenetic modifications of several genes occur in the average CRC genome. Therefore, the current opinion is that CRCs are the consequence of the accumulation of both mutations and epigenetic modifications of several genes. This mini-review article focuses on DNA methylation biomarkers in CRC. Recent large-scale DNA methylation studies suggest that CRCs can be divided into at least three-four subtypes according to the frequency of DNA methylation and those of mutations in key CRC genes. Despite hundreds of genes might be epigenetically modified in CRC cells, there is interest in the identification of DNA methylation biomarkers to be used for CRC diagnosis, progression, tendency to tissue invasion and metastasis, prognosis, and response to chemotherapeutic agents. Moreover, DNA methylation largely depends on one-carbon metabolism, the metabolic pathway required for the production of S-adenosylmethionine, the major intracellular methylating agent. Complex interactions are emerging among dietary one-carbon nutrients (folates, vitamin B6, vitamin B12, methionine, and others), their metabolic genes, CRC risk, and DNA methylation profiles in CRC. Moreover, active research is also focused on the possible contribution of folic acid dietary fortification during pregnancy and the possible methylation of CRC-related genes in the offspring.     

甲状腺癌的DNA甲基化研究进展

DNA甲基化是一种重要的表观遗传学改变,在肿瘤的发病、诊断、预后评估及治疗中都有重要的临床意义.甲状腺癌是临床最常见的内分泌系统恶性肿瘤,目前国内外关于甲状腺癌的DNA甲基化的研究相对较少,该文总结近年来甲状腺癌领域相关的基因甲基化研究,就甲状腺癌的DNA甲基化研究进展进行综述.     

Insights into the epigenetic mechanisms controlling pancreatic carcinogenesis

During the last couple decades, we have significantly advanced our understanding of mechanisms underlying the development of pancreatic ductual adenocarcinoma (PDAC). In the late 1990s into the early 2000s, a model of PDAC development and progression was developed as a multi-step process associated with the accumulation of somatic mutations. The correlation and association of these particular genetic aberrations with the establishment and progression of PDAC has revolutionized our understanding of this process. However, this model leaves out other molecular events involved in PDAC pathogenesis that contribute to its development and maintenance, specifically those being epigenetic events. Thus, a new model considering the new scientific paradigms of epigenetics will provide a more comprehensive and useful framework for understanding the pathophysiological mechanisms underlying this disease. Epigenetics is defined as the type of inheritance not based on a particular DNA sequence but rather traits that are passed to the next generation via DNA and histone modifications as well as microRNA-dependent mechanisms. Key tumor suppressors that are well established to play a role in PDAC may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. A noteworthy characteristic of epigenetic-based inheritance is its reversibility, which is in contrast to the stable nature of DNA sequence-based alterations. Given this nature of epigenetic alterations, it becomes imperative that our understanding of epigenetic-based events promoting and maintaining PDAC continues to grow.     

基因启动子区甲基化与结直肠癌研究进展

近年来研究表明,表观遗传修饰的ＤＮＡ甲基化在结直肠癌的发生发展中具有重要的作用。在结直肠癌中普遍存在ＤＮＡ甲基化,对于肿瘤的早期诊断具有重要的指导意义。因为ＤＮＡ甲基化的可逆性,可能为肿瘤的治疗提供靶点。从ＤＮＡ甲基化方面寻找预测结直肠癌药物疗效的分子标志物,有可能成为推动结直肠癌个体化治疗的新方向。     

肿瘤中自噬的表观遗传学研究进展

自噬是指真核细胞生物在代谢压力下,细胞自身胞质成分被双层膜结构的自噬小泡包裹后运送至溶酶体融合降解的过程。越来越多的研究证据表明,自噬在肿瘤的发生、发展中发挥着重要作用。本研究就肿瘤中自噬的发生、发展亦存在的多种表观遗传学研究进展作一综述。     

Bevacizumab-based therapies in the first-line treatment of metastatic colorectal cancer

Since its approval for the first-line treatment of metastatic colorectal cancer (mCRC), bevacizumab has become a standard treatment option in combination with chemotherapy for patients with mCRC. Bevacizumab has demonstrated efficacy in combination with a number of different backbone chemotherapy regimens, and its widespread use has introduced several important questions regarding the selection and optimization of bevacizumab-based treatment regimens, its use in various patient populations, and the identification of associated adverse events. This review discusses the results of several phase II and phase III clinical trials, as well as large observational studies, to address the use of bevacizumab in the treatment of patients with mCRC in the first-line setting.     

外周血USP1基因甲基化与大肠癌预后风险的关系

目的 探讨外周血中去泛素化酶USP1甲基化及临床特征与大肠癌预后风险的关系。方法 采用队列研究,共纳入286例大肠癌患者。使用高分辨率熔解曲线分析法(HRM)检测基因甲基化水平。应用Cox回归模型评估基因甲基化及临床特征与大肠癌预后风险之间的关联。结果 在男性大肠癌病例中,USP1甲基化增加预后不良风险(HR=2.091,95% CI:1.195~3.661,P=0.010)。临床病理特征中,UICC肿瘤分期4期(HR=2.464,95% CI:1.205~5.039,P=0.014)、肿瘤大小超过50mm(HR=1.610,95% CI:1.016~2.550,P=0.043)和组织学非腺型(HR=5.117,95% CI:1.142~22.930,P=0.033)是大肠癌不良预后风险增加的影响因素。结论 UICC肿瘤分期4期、肿瘤大小超过50mm和组织学分型为非腺型会增加大肠癌不良预后风险。外周血USP1基因启动子区甲基化与男性大肠癌预后不良风险增加有关。     

Acquired resistance to EGFR-targeted therapies in colorectal cancer

Cetuximab and panitumumab are anti‐epidermal growth factor receptor (anti‐EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3–12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti‐EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR‐RAS‐RAF‐MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti‐EGFR antibodies. The escape from anti‐EGFR blockade appears to converge on the (re)activation of MEK‐ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti‐EGFR therapy and test combination therapies to overcome or reverse resistance.