Molecular and cell phenotype programs in oral epithelial cells directed by co-exposure to arsenic and smokeless tobacco.

Chronic arsenic exposure can lead to various health issues, including cancer. Concerns have been mounting about the enhancement of arsenic toxicity through co-exposure to various prevalent lifestyle habits. Smokeless tobacco products are commonly consumed in South Asian countries, where their use frequently co-occurs with exposure to arsenic from contaminated groundwater.

Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth.

Background: Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium.

Waterpipe and cigarette epigenome analysis reveals markers implicated in addiction and smoking type inference.

Waterpipe smoking is frequent in the Middle East and Africa with emerging prevalence worldwide. The epigenome acts as a molecular sensor to exposures and a crucial driver in several diseases. With the widespread use of waterpipe smoking, it is timely to investigate its epigenomic markers and their role in addiction, as a central player in disease prevention and therapeutic strategies.

Buffy coat signatures of breast cancer risk in a prospective cohort study.

Background: Epigenetic alterations are a near-universal feature of human malignancy and have been detected in malignant cells as well as in easily accessible specimens such as blood and urine. These findings offer promising applications in cancer detection, subtyping, and treatment monitoring. However, much of the current evidence is based on findings in retrospective studies and may reflect epigenetic patterns that have already been influenced by the onset of the disease.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile.

Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.

Background: Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming.

Methods: Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003).

Lessons learned from the discovery and development of the sesquiterpene lactones in cancer therapy and prevention.

Introduction: Sesquiterpene lactones (SLs) are one of the most diverse bioactive secondary metabolites found in plants and exhibit a broad range of therapeutic properties . SLs have been showing promising potential in cancer clinical trials, and the molecular mechanisms underlying their anticancer potential are being uncovered. Recent evidence also points to a potential utility of SLs in cancer prevention.

Interrelationships and determinants of aging biomarkers in cord blood.

Background: Increasing evidence supports the concept of prenatal programming as an early factor in the aging process. DNA methylation age (DNAm age), global genome-wide DNA methylation (global methylation), telomere length (TL), and mitochondrial DNA content (mtDNA content) have independently been shown to be markers of aging, but their interrelationship and determinants at birth remain uncertain.

Methods: We assessed the inter-correlation between the aging biomarkers DNAm age, global methylation, TL and mtDNA content using Pearson's correlation in 190 cord blood samples of the ENVIRONAGE birth cohort.

Cutaneous and acral melanoma cross-OMICs reveals prognostic cancer drivers associated with pathobiology and ultraviolet exposure.

Ultraviolet radiation (UV) is causally linked to cutaneous melanoma, yet the underlying epigenetic mechanisms, known as molecular sensors of exposure, have not been characterized in clinical biospecimens. Here, we integrate clinical, epigenome (DNA methylome), genome and transcriptome profiling of 112 cutaneous melanoma from two multi-ethnic cohorts. We identify UV-related alterations in regulatory regions and immunological pathways, with multi-OMICs cancer driver potential affecting patient survival.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits.

Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium.

Aflatoxin Exposure during Early Life Is Associated with Differential DNA Methylation in Two-Year-Old Gambian Children.

: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers' blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. : Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population ( = 244), in relation to the child's dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age.

LINE-1 methylation mediates the inverse association between body mass index and breast cancer risk: A pilot study in the Lebanese population.

Introduction: Lebanon is among the top countries worldwide in combined incidence and mortality of breast cancer, which raises concern about risk factors peculiar to this country. The underlying molecular mechanisms of breast cancer require elucidation, particularly epigenetics, which is recognized as a molecular sensor to environmental exposures.

Purpose: We aim to explore whether DNA methylation levels of AHRR (marker of cigarette smoking), SLC1A5 and TXLNA (markers of alcohol consumption), and LINE-1 (a genome-wide repetitive retrotransposon) can act as molecular mediators underlying putative associations between breast cancer risk and pertinent extrinsic (tobacco smoking and alcohol consumption) and intrinsic factors [age and body mass index (BMI)].

Paternal Exposure to Non-essential Heavy Metal Affects Embryo Cleavage and Implantation in Intracytoplasmic Sperm Injection (ICSI) Cycles: Evidence for a Paradoxical Effect.

Although the adverse effects of non-essential heavy metals on semen quality have been demonstrated in experimental animal models and occupational human exposure studies, little is known about the reproductive efficiency of exposed sperm during the process of intracytoplasmic sperm injection (ICSI). Our study aims to evaluate the effect of paternal exposure to non-essential heavy metals on embryo efficiency outcomes (embryo cleavage, fragmentation, implantation, and live birth) in ICSI cycle. Ninety-five heterosexual couples who underwent 95 ICSI cycles and 78 fresh embryo transfers between January 2003 and December 2009 were evaluated.

Paternal body mass index and offspring DNA methylation: findings from the PACE consortium.

Background: Accumulating evidence links paternal adiposity in the periconceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very few studies have explored this possibility in humans.

Methods: In the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of coordinated epigenome-wide association studies (EWAS) of paternal prenatal body mass index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 data sets; total n = 4894) and in childhood (6 data sets; total n = 1982).

DNA methylation of insulin-like growth factor 2 and H19 cluster in cord blood and prenatal air pollution exposure to fine particulate matter.

Background: The IGF2 (insulin-like growth factor 2) and H19 gene cluster plays an important role during pregnancy as it promotes both foetal and placental growth. We investigated the association between cord blood DNA methylation status of the IGF2/H19 gene cluster and maternal fine particulate matter exposure during fetal life. To the best of our knowledge, this is the first study investigating the association between prenatal PM exposure and newborn DNA methylation of the IGF2/H19.

A molecular map of lung neuroendocrine neoplasms.

Background: Lung neuroendocrine neoplasms (LNENs) are rare solid cancers, with most genomic studies including a limited number of samples. Recently, generating the first multi-omic dataset for atypical pulmonary carcinoids and the first methylation dataset for large-cell neuroendocrine carcinomas led us to the discovery of clinically relevant molecular groups, as well as a new entity of pulmonary carcinoids (supra-carcinoids).

Results: To promote the integration of LNENs molecular data, we provide here detailed information on data generation and quality control for whole-genome/exome sequencing, RNA sequencing, and EPIC 850K methylation arrays for a total of 84 patients with LNENs.

Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes.

The recent identification of recurrently mutated epigenetic regulator genes (ERGs) supports their critical role in tumorigenesis. We conducted a pan-cancer analysis integrating (epi)genome, transcriptome, and DNA methylome alterations in a curated list of 426 ERGs across 33 cancer types, comprising 10,845 tumor and 730 normal tissues. We found that, in addition to mutations, copy number alterations in ERGs were more frequent than previously anticipated and tightly linked to expression aberrations.

A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.

Methods: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489).

Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study.

Background: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease.

Objective: We performed mutually independent EWAS on transportation noise and air pollution exposures.

Methods: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations.

Effect of bisphenols on telomerase expression and activity in breast cancer cell lines.

Bisphenol A (BPA), a monomer of polycarbonates and resins, was shown to induce the expression of telomerase enzyme which has been associated with breast cancer development and progression. However, the effects of BPA analogues, bisphenol F (BPF) and bisphenol S (BPS) on telomere-linked pathway have not been evaluated. Herein, MCF-7 (estrogen receptor (ER)-positive) and MDA-MB-231 (ER-negative) cells were treated with BPA, BPF and BPS ± estrogen receptor inhibitor (ERI), for 24 and/or 48 h.

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section.