Obesity Abstract Obesity is a heterogeneous disease with many different subtypes. Epigenetics could contribute to these differences. The aim of this study was to investigate genome-wide DNA methylation searching for methylation marks associated with obesity in children and adolescents. After correction for cell heterogeneity and multiple tests, we found that compared to lean controls, 31 CpGs are differentially methylated in obese patients. A greatest proportion of these CpGs is hypermethylated in obesity and located in CpG shores regions.
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Therefore, it is possible to use epigenetic marks as biomarkers for predictive and precision medicine in cancer. Precision medicine is poised to impact clinical practice, patients, and healthcare systems. The objective of this review is to provide an overview of the epigenetic testing landscape in cancer by examining commercially available epigenetic-based in vitro diagnostic tests for colon, breast, cervical, glioblastoma, lung cancers, and for cancers of unknown origin.
We compile current commercial epigenetic tests based on epigenetic biomarkers i. Introduction Epigenetics, a breakthrough discipline in biomedicine, aims to improve precision medicine by discovering new epigenetic mechanisms and providing new epigenetic biomarkers, therapeutic targets, and epigenetic drugs with potential uses in clinical practice.
Most human diseases have complex multifactorial pathologies that result from a pathogenic polymorphism in human genes, besides epigenetic mechanisms, which can modulate the expression of functional genes.
Currently, several IVD molecular-based tests contribute to the development of precision oncology, which already offers viable alternatives for cancer diagnostics and prognostics. For a given phenotype, there is a causal contribution of genetic mutations, copy number variations, epigenetic control, and altered transcription programs and altered complex metabolic inputs.
The contribution of the aforementioned factors renders the use of different approaches necessary to understand the physiopathology of complex and multifactorial diseases. In line with this, epigenetic biomarkers can help early diagnosis, disease progression monitoring, disease outcome prediction, selection and stratification of patients by risk, prediction of future comorbidities, and even the evaluation of the positive or negative effects of therapeutic interventions in specific patient subsets.
Among others, DNA methylation and microRNAs are markedly more stable than RNA and proteins, which renders the use of these biomarkers more practical and viable in clinical settings Faruq and Vecchione, ; Hashimoto et al. In particular, DNA methylation, microRNAs, and post-translational modifications of histones offer high stability in biofluids and in samples with a compromised quality, such as formalin-fixed paraffin embedded FFPE. Other advantages of epigenetic biomarkers over genetic or protein-based biomarkers are as follows: 1 their dynamic nature; 2 they provide information about the gene function; 3 they inform about the specific genetic programs that alter during disease; and 4 most techniques to analyze epigenetic biomarkers i.
Therefore, epigenetics has a tremendous potential to improve predictive and precision medicine. Therefore, precision medicine has started to use potential epigenetic biomarkers in clinical settings. However, for clinical settings, minimal invasive procedures are preferable. To achieve the precision medicine goals, the current challenge is knowing how to obtain a reliable useful biomarker for clinical routine because, for this purpose, the new biomarker requires high accuracy and robustness Li et al.
This low percentage of commercialized IVD tests based on epigenetic biomarkers suggests that the precision medicine ecosystem formed by distinct stakeholders i. A number of precision medicine applications are contributing to health care improvements by allowing the precise diagnosis of diseases or by identifying specific disease subsets or stages, and by also improving personalized treatments. Specifically, for cancer, which remains the second leading cause of death worldwide, early detection, the identification of cancer subtypes, and the selection of appropriate therapies are crucial to increase the survival of cancer patients.
However, the identification of new tumor biomarkers, especially those based on epigenetic biomarkers with the capability to identify tumor origin or cancer subsets, advances in assay technologies, and the development of sophisticated analytical software techniques i. Technologies for Epigenetic Biomarker Analyses in Clinical Laboratories Given the prevalence of the DNA methylation alterations at specific genes under a variety of human disease conditions, a promising future is coming for the DNA methylation analysis as an epigenetic biomarker.
In fact, DNA methylation is the best-studied epigenetic modification since it was discovered. In addition, miRNAs have attracted a great deal of interest in clinical research for their role in gene regulation, tissue signaling and cellular homeostasis, their high stability in practically all types of biospecimens, and the relatively easy way by which to measure miRNAs in a wide array of biospecimens. Histone variants and histone post-translational modifications are other potential markers that can be analyzed in a wide array of biospecimens for clinical settings.
Therefore, it is not surprising that most current commercial in vitro diagnostic tests are based on either the analysis of DNA methylation of specific genes or the measurement of the relative expression of microRNAs, which can be easily measured by RT-qPCR-based methods i.
There are other assays based on high-throughput analyses to simultaneously measure several CpG sites. In the following section, we provide details of a selection of current IVD tests based on epigenetic biomarkers that are currently being commercialized for in vitro diagnostic in cancer Table 1.
CRC is the second leading cause of death by cancer. CRC is characterized by slow progression from detectable precancerous lesions and has a good prognosis when patients are diagnosed in early stages.
Therefore, the potential for reducing the burden of CRC by early detection is significant, and efforts are currently being made to develop CRC screening tests and to improve the adherence rates of participation for screening because people scarcely comply with currently available methods Issa and Noureddine, The selection of appropriate therapies for CRC patients is also a clinical need.
So, the identification of additional biomarkers to allow clinicians to select those patients who could benefit by the established therapies is needed. In fact, the sensitivity for detecting advanced precancerous lesions was However, its high cost and difficult sample pretreatment and management for each analysis type are considered disadvantages for its rapid implementation into clinical routine. One noteworthy result was that the positive detection rate of the SEPT9 methylation assay increased exponentially as colorectal lesions became more severe and with more advanced CRC stages Song et al.
The results obtained by Song et al. These scenarios suggest the potential of this test to diagnose other cancers, such as breast cancer, as demonstrated by Shen et al. It is worth mentioning that colonoscopy remains the universal gold standard method for CRC diagnostics. However, Chinese guidelines have recently recommended using the test as a complement to other diagnostic approaches, like the guaiac-based gFOBT.
Previous studies have demonstrated the potential of the analysis of the methylation status of the SDC2 gene for the early diagnosis of CRC. For example, the studies performed by Mitchell et al. At this point, it is worth mentioning that the amplicon selected to study the methylation status of this gene slightly differed bp downstream to the CpG proposed by Oh et al.
More recent studies performed by Oh et al. Similarly, Niu et al. These results were comparable to that observed by Park et al. Of the evaluated subjects, had CRC, 44 had various sized adenomatous polyps, and obtained negative colonoscopy results.
The sensitivity for detecting early stages 0-II was Genomictree Inc. In this study, the sensitivity was The methylation positivity for SDC2 was observed in Notably, sensitivity was Furthermore, the miRp expression was evaluated for its potential as a predictive biomarker for anti-EGFR mAb therapy in the patients without mutations in KRAS with operable colorectal liver metastases Pugh et al.
In an interventional clinical trial in 1, subjects ClinicalTrials. More recently with logistic regression models, including the miRp expression level adjusted for potential confounding factors, Laurent-Puig et al. Those patients with low miRp levels showed better outcomes when treated with cetuximab compared with bevacizumab.
These results demonstrated the good versatility of the miRpredXp assay and its feasibility for being easily implemented into clinical diagnostic laboratories. Hence the miRpredXp assay can analyze up to 12 samples and provide the results in 1 day see version 8 of the mirpredx instructions manual. The Nu. The most advanced test is the Nu. In a validation study performed by Holdenrieder et al. Holdenrieder et al.
The AUC on the receiver operating characteristic curve was 0. To improve both the sensitivity and specificity of the assays, two new tests were designed: the Nu. Rahier et al. The multivariate analysis defined a panel of four age-adjusted cf-nucleosomes that provided an AUC of 0. The second combination of four cf-nucleosome biomarkers provided an AUC of 0.
Moreover, the test detected The results of this large cohort evaluation were promising as the Nu. The Volition Company announced that the new Nu. Furthermore, the new Nu. The Volition Company is developing new-generation Nu. Q assays for other intended uses, such as pancreatic cancer. In fact the Nu. Q assay was also evaluated for the diagnostic of pancreatic cancer.
By using a combination of carbohydrate antigen CA levels with a panel of four cf-nucleosome markers, Bauden et al. It is noteworthy that breast cancer can also affect men and, consequently, around 2, new cases of invasive breast cancer are expected to be diagnosed in men in In addition, screening with the mammography technique has demonstrated its ability to detect breast cancer in early stages, which reduces the mortality risk and increases treatment success Lauby-Secretan et al.
As a result, new methods that contribute to early diagnosis, the identification of specific subtypes, and the selection of patients who can benefit from specific therapies will increase patient survival for this cancer. Breast cancer mortality also depends on the cancer subtype. Breast cancer presents several classifications depending on different aspects. It can be classified according to their histological origin, cell differentiation degree, stage, the presence or absence of certain hormone receptors [i.
Tumors classified as triple-negative breast cancer TNBC and HER2-positive breast cancer are classified as high-risk cancer with a poor prognosis Harbeck and Gnant, Enhancing breast cancer survival and outcome by early detection remains one of the main breast cancer priorities according to the World Health Organization WHO.
Therefore, several efforts are being made by the research community to provide not only new drugs and therapies to treat breast cancer, but to also identify new biomarkers to help implement precision medicine into the clinical management of breast cancer patients Low et al. Breast cancer treatment depends partially on the disease state and the breast cancer subtype. Generally speaking, the commonest treatments are targeted therapy, hormonal therapy, radiation therapy, surgery, and chemotherapy, although immunotherapy is being increasingly utilized.
Fortunately, the therapeutic options for breast cancer patients are further improved thanks to the use of biomarkers and the implementation of precision medicine Meisel et al. The test differentiates between the patients more likely to respond to anthracyclines chemotherapy Aubele et al.
The methylation analysis of PITX2 a promoter of transcription factor 2 of the pituitary homeobox demonstrates a high correlation with other diagnostic techniques, has the predictive and prognostic capability for patient identification, and supports clinicians by being the most effective therapy option.
PITX2 methylation has attracted the attention of clinicians for not only breast cancer Widschwendter et al. Continuous scientific evidence indicates the potential of the PITX2 methylation analysis to predict breast cancer outcomes in lymph node-positive, ER-positive, and HER2-negative breast cancer patients to adjuvant anthracycline-based chemotherapy. Therefore, these clinical observations reinforce the idea of using PITX2 methylation status to support clinicians as the most effective therapy option Hartmann et al.
Hartmann et al. PITX2 plays an essential role in the disease pathogenesis. In fact, tumors with a hypermethylated PITX2 status correlate with poorer survival overall survival and reduced metastasis-free survival , and also with resistance to treatment. In addition, PITX2 methylation has been associated with the response to adjuvant chemotherapy Absmaier et al.
Absmaier et al. To do so, these authors determined the PITX2 DNA methylation status in non-metastatic TNBC patients treated with adjuvant chemotherapy with anthracycline by a molecular analysis of breast cancer tissues.
Genome-Wide Methylation Analysis Identifies Specific Epigenetic Marks In Severely Obese Children
So, of course any book with the title of Epigenetics is going to grab our attention. The chapters found in this text covers: biological mechanisms and epigenetic machinery like DNA methylation, histone tails, chromatin structure, nucleosome occupancy, Polycomb group proteins, siRNAs and miRNAs; the epigenetic systems of plants, embryonic stem cells, cell differentiation, imprinting marks, and random X chromosome inactivation; epigenetics in cancers, premature aging, longevity and the developmental origins of disease and the transfer of epigenetic information across generations. Here are some bite-sized looks at chapters that we found to be especially intriguing. Carrozza Chromatin structure and modification is being shown to have a significant role in many processes involving DNA. Histone variants H3. Z, gammaH2A. Bbd, H1 variants and testis specific variants are covered in this section as well as the functions associated with these variants, plus nucleosome occupancy levels found throughout the eukaryotic genome.
Epigenetic IVD Tests for Personalized Precision Medicine in Cancer
Kami The reason for the greater epigenetic complexity in plants is not simply their multicellular development but also their need to cope with an ever-changing environment due to their sessile lifestyle. Polycomb and Trithorax group proteins have long been known as epigfnetics epigenetic regulators of homeotic genes. Longevity, Epigenetics and Cancer. The field of epigenetics epigenstics gained great momentum in recent years and is now a rapidly advancing field of biological and medical research. Besides its role in the regulation of genes, DNA methylation silences repetitive elements and appears to be important for the stability of the mammalian genome.
EpiGenie Book Reviews: Epigenetics
Epigenetic changes play a key role in normal development, as well as in disease. The editor of this book has assembled top-quality scientists from diverse fields of epigenetics to produce a major new volume on current epigenetics research. The molecular mechanisms and biological processes in which epigenetic modifications play a primordial role are described in detail. The first seven chapters describe the different biological mechanisms of the epigenetic machinery including: DNA methylation, histone tails, chromatin structure, nucleosome occupancy, Polycomb group proteins, siRNAs, and miRNAs. The following chapters cover the epigenetic systems of plants, the epigenetic profile of embryonic stem cells, cell differentiation, imprinting marks, and random X chromosome inactivation. Further chapters deal with epigenetics in relation to cancers, premature aging, longevity, and the developmental origins of disease. The final chapter describes the fascinating potential transfer of epigenetic information across generations.