Abstract:
BACKGROUND:Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. RESULTS:Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. CONCLUSIONS:Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.
journal_name
Clin Epigeneticsjournal_title
Clinical epigeneticsauthors
Lee JJ,Sholl LM,Lindeman NI,Granter SR,Laga AC,Shivdasani P,Chin G,Luke JJ,Ott PA,Hodi FS,Mihm MC Jr,Lin JY,Werchniak AE,Haynes HA,Bailey N,Liu R,Murphy GF,Lian CGdoi
10.1186/s13148-015-0091-3subject
Has Abstractpub_date
2015-06-09 00:00:00pages
59eissn
1868-7075issn
1868-7083pii
91journal_volume
7pub_type
杂志文章abstract:BACKGROUND:Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whet...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-019-0798-7
更新日期:2020-01-13 00:00:00
abstract:BACKGROUND:ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methyl...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-019-0658-5
更新日期:2019-04-27 00:00:00
abstract:BACKGROUND:Zinc-finger protein 471 (ZNF471) is a member of the Krüppel-associated box domain zinc finger protein (KRAB-ZFP) family. ZNF471 is methylated in squamous cell carcinomas of tongue, stomach and esophageal. However, its role in breast carcinogenesis remains elusive. Here, we studied its expression, functions, ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-020-00959-6
更新日期:2020-11-17 00:00:00
abstract:BACKGROUND:Epigenetic changes in DNA methylation could regulate the expression of several allergy-related genes. We investigated whether tolerance acquisition in children with immunoglobulin E (IgE)-mediated cow's milk allergy (CMA) is characterized by a specific DNA methylation profile of Th2 (IL-4, IL-5) and Th1 (IL-...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-015-0070-8
更新日期:2015-03-31 00:00:00
abstract:BACKGROUND:Insufficient specificity of the high-risk human papillomavirus (hrHPV) assay in primary cervical cancer screening results in unnecessary referral. Additional assays to triage hrHPV-positive women are needed to improve molecular cervical cancer screening. DNA methylation is a promising biomarker in cervical c...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-015-0122-0
更新日期:2015-08-21 00:00:00
abstract:Background:New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HD...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-017-0434-3
更新日期:2018-01-04 00:00:00
abstract:BACKGROUND:Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that o...
journal_title:Clinical epigenetics
pub_type: 杂志文章,多中心研究
doi:10.1186/s13148-018-0534-8
更新日期:2018-08-29 00:00:00
abstract:BACKGROUND:Cancer treatments have substantially improved childhood cancer survival but are accompanied by long-term complications, notably chronic inflammatory diseases. We hypothesize that cancer treatments could lead to long-term epigenetic changes in immune cells, resulting in increased prevalence of inflammatory di...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0561-5
更新日期:2018-11-06 00:00:00
abstract:BACKGROUND:The birth weight of Black neonates in the United States is consistently smaller than that of their White counterparts. Epigenetic differences between the races may be involved in such disparities. The goal of these analyses was to model the role of IGF1 methylation in mediating the association between race a...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-015-0080-6
更新日期:2015-04-21 00:00:00
abstract:Background:The dynamic methylation of human papillomavirus (HPV) 16 DNA is thought to be associated with the progression of cervical lesions. Previous studies that did not consider the physical status of HPV 16 may have incorrectly mapped HPV 16 methylomes. In order to identify reliable biomarkers for squamous cervical...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0445-8
更新日期:2018-01-23 00:00:00
abstract:BACKGROUND:The prevalence of type 2 diabetes (T2D) and obesity has dramatically increased within a few generations, reaching epidemic levels. In addition to genetic risk factors, epigenetic mechanisms triggered by changing environment are investigated for their role in the pathogenesis of these complex diseases. Epigen...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-016-0177-6
更新日期:2016-01-28 00:00:00
abstract:BACKGROUND:Prostate cancer (PC) is a commonly diagnosed malignancy in males, especially in the western hemisphere. The extensive use of multiple biomarkers plays an important role in the diagnosis and prognosis of PC. However, the accuracy of biomarkers for PC prognosis needs to be urgently improved. This study aimed t...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-019-0693-2
更新日期:2019-07-09 00:00:00
abstract:BACKGROUND:The recent discovery of cancer/tissue specificity of miRNA has indicated its great potential as a therapeutic target. In Epstein-Barr virus-associated gastric cancer (EBVaGC), host genes are affected by extensive DNA methylation, including miRNAs. However, the role of methylated miRNA in the development of E...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-020-00989-0
更新日期:2021-01-29 00:00:00
abstract:BACKGROUND:Goblet cell metaplasia, a common feature of chronic obstructive pulmonary disease (COPD), is associated with mucus hypersecretion which contributes to the morbidity and mortality among patients. Transcription factors SAM-pointed domain-containing Ets-like factor (SPDEF) and forkhead box protein A2 (FOXA2) re...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-017-0341-7
更新日期:2017-04-24 00:00:00
abstract:BACKGROUND:Epigenetic mechanisms are thought to be critical in mediating the role of the intrauterine environment on lifelong health and disease. Twin-twin transfusion syndrome (TTTS) is a rare condition wherein fetuses share the placenta and develop vascular anastomoses, which allow blood to flow between the fetuses. ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/1868-7083-5-18
更新日期:2013-10-03 00:00:00
abstract:BACKGROUND:Obesity and diabetes mellitus are directly implicated in many adverse health consequences in adults as well as in the offspring of obese and diabetic mothers. Hispanic Americans are particularly at risk for obesity, diabetes, and end-stage renal disease. Maternal obesity and/or diabetes through prenatal prog...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-020-0824-9
更新日期:2020-02-19 00:00:00
abstract:BACKGROUND:Preterm birth (PTB), defined as child birth before completion of 37 weeks of gestation, is a major challenge in perinatal health care and can bear long-term medical and financial burden. Over a million children die each year due to PTB complications, and those who survive can face developmental delays. Unfor...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0599-4
更新日期:2019-02-11 00:00:00
abstract:INTRODUCTION:DNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). In cancer cells, global hypomethylation of the genome as a whole and regional hypermethylation...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/1868-7083-5-7
更新日期:2013-05-02 00:00:00
abstract:BACKGROUND:Smoking is the largest preventable cause of morbidity and mortality in the United States. In previous work, we demonstrated that altered DNA methylation at the aryl hydrocarbon receptor repressor (AHRR) is correlated with self-reported smoking in 19-year-old African Americans with relatively low levels of sm...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/1868-7083-5-19
更新日期:2013-10-11 00:00:00
abstract:BACKGROUND:Colorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from host immunosurveillance. Changes in DNA methylation pattern and enrichm...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0539-3
更新日期:2018-08-06 00:00:00
abstract:BACKGROUND:Activation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. However, very few studies have systematically identified the enhancers specific in cancer tissues. METHODS:Here, we studied the change of histone modifications in MMTV-PyVT breast ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-019-0645-x
更新日期:2019-03-12 00:00:00
abstract:: Friedreich ataxia (FRDA) is a debilitating and frequently fatal neurological disorder that is recessively inherited. It belongs to the group of genetic disorders known as the Repeat Expansion Diseases, in which pathology arises from the deleterious consequences of the inheritance of a tandem repeat array whose repeat...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/1868-7083-4-2
更新日期:2012-01-30 00:00:00
abstract::Researchers have begun to examine epigenetic alterations in the placenta, making key advances in understanding the epigenetic regulatory mechanisms of the placenta that define underlying processes of human development and disease. Examining changes in microRNA (miRNA) expression associated with environmental exposures...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1007/s13148-011-0046-2
更新日期:2011-08-01 00:00:00
abstract::In this letter to the editor, we highlight some concerns with a recently published method to estimate gestational age at delivery from DNA methylation data. We conduct novel analyses to highlight the implications of different choices in study design and statistical methods for the prediction of phenotypes from methyla...
journal_title:Clinical epigenetics
pub_type: 信件
doi:10.1186/s13148-017-0402-y
更新日期:2017-09-15 00:00:00
abstract:Background:AXL is one of the TAM (TYRO3, AXL and MERTK) receptor tyrosine kinases and may affect numerous immune-related health conditions. However, the role for AXL in asthma, including its epigenetic regulation, has not been extensively studied. Methods:We investigated the association between AXL DNA methylation at ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-017-0421-8
更新日期:2017-11-07 00:00:00
abstract::Remodeling of the sperm epigenome by lifestyle factors before conception could account for altered metabolism in the next generation offspring. Here, we hypothesized that endurance training changes the epigenome of human spermatozoa. Using small RNA (sRNA) sequencing and reduced representation bisulfite sequencing (RR...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0446-7
更新日期:2018-01-25 00:00:00
abstract:BACKGROUND:Adiponectin critically contributes to metabolic homeostasis, especially by insulin-sensitizing action. Gestational diabetes mellitus (GDM) is characterized by insulin resistance leading to materno-fetal hyperglycemia and detrimental birth outcomes. By investigating paired subcutaneous (SAT) and visceral adip...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-018-0567-z
更新日期:2018-10-24 00:00:00
abstract:BACKGROUND:The DNA modification 5-hydroxymethylcytosine (5hmC) is now referred to as the sixth base of DNA with evidence of tissue-specific patterns and correlation with gene regulation and expression. This epigenetic mark was recently reported as a potential biomarker for multiple types of cancer, but its application ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-017-0368-9
更新日期:2017-07-14 00:00:00
abstract:: Lower than normal levels of oxygen (hypoxia) is a hallmark of all solid tumours rendering them frequently resistant to both radiotherapy and chemotherapy regimes. Furthermore, tumour hypoxia and activation of the hypoxia inducible factor (HIF) transcriptional pathway is associated with poorer prognosis. Driven by bot...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/1868-7083-3-9
更新日期:2011-12-05 00:00:00
abstract:BACKGROUND:DNA methylation is a well-studied epigenetic mark that is frequently altered in diseases such as cancer, where specific changes are known to reflect the type and severity of the disease. Therefore, there is a growing interest in assessing the clinical utility of DNA methylation as a biomarker for diagnosing ...
journal_title:Clinical epigenetics
pub_type: 杂志文章
doi:10.1186/s13148-020-00880-y
更新日期:2020-06-22 00:00:00