DNA methylation markers for risk of metastasis in a cohort of men with localized prostate cancer.

Accurately identifying life-threatening prostate cancer (PCa) at time of diagnosis remains an unsolved problem. We evaluated whether DNA methylation status of selected candidate genes can predict the risk of metastasis beyond clinical risk factors in men with untreated PCa. A nested case-control study was conducted among men diagnosed with localized PCa at Kaiser Permanente California between 01/01/1997-12/31/2006 who did not receive curative treatments.

Genome-wide methylation profiling of diagnostic tumor specimens identified DNA methylation markers associated with metastasis among men with untreated localized prostate cancer.

Background: We used a genome-wide discovery approach to identify methylation markers associated with metastasis in men with localized prostate cancer (PCa), as better identification of those at high risk of metastasis can inform treatment decision-making.

Methods: We identified men with localized PCa at Kaiser Permanente California (January 1, 1997-December 31, 2006) who did not receive curative treatment and followed them for 10 years to determine metastasis status. Cases were chart review-confirmed metastasis, and controls were matched using density sampling.

Cell-free DNA Methylation as a Predictive Biomarker of Response to Neoadjuvant Chemotherapy for Patients with Muscle-invasive Bladder Cancer in SWOG S1314.

Background: Neoadjuvant chemotherapy (NAC) is the standard of care in muscle-invasive bladder cancer (MIBC). However, treatment is intense, and the overall benefit is small, necessitating effective biomarkers to identify patients who will benefit most.

Objective: To characterize cell-free DNA (cfDNA) methylation in patients receiving NAC in SWOG S1314, a prospective cooperative group trial, and to correlate the methylation signatures with pathologic response at radical cystectomy.

Integrated DNA Methylation/RNA Profiling in Middle Temporal Gyrus of Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disorder clinically defined by gradual cognitive impairment and alteration in executive function. We conducted an epigenome-wide association study (EWAS) of a clinically and neuropathologically characterized cohort of 296 brains, including Alzheimer's disease (AD) and non-demented controls (ND), exploring the relationship with the RNA expression from matched donors. We detected 5246 CpGs and 832 regions differentially methylated, finding overlap with previous EWAS but also new associations.

DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia.

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia.

A novel role for vaping in mitochondrial gene dysregulation and inflammation fundamental to disease development.

We constructed and analyzed the whole transcriptome in leukocytes of healthy adult vapers (with/without a history of smoking), 'exclusive' cigarette smokers, and controls (non-users of any tobacco products). Furthermore, we performed single-gene validation of expression data, and biochemical validation of vaping/smoking status by plasma cotinine measurement. Computational modeling, combining primary analysis (age- and sex-adjusted limmaVoom) and sensitivity analysis (cumulative e-liquid- and pack-year modeling), revealed that 'current' vaping, but not 'past' smoking, is significantly associated with gene dysregulation in vapers.

Functional human genes typically exhibit epigenetic conservation.

Recent DepMap CRISPR-Cas9 single gene disruptions have identified genes more essential to proliferation in tissue culture. It would be valuable to translate these finding with measurements more practical for human tissues. Here we show that DepMap essential genes and other literature curated functional genes exhibit cell-specific preferential epigenetic conservation when DNA methylation measurements are compared between replicate cell lines and between intestinal crypts from the same individual.

Inter-individual variability in structural brain development from late childhood to young adulthood.

A fundamental task in neuroscience is to characterize the brain's developmental course. While replicable group-level models of structural brain development from childhood to adulthood have recently been identified, we have yet to quantify and understand individual differences in structural brain development. The present study examined inter-individual variability and sex differences in changes in brain structure, as assessed by anatomical MRI, across ages 8.

A Novel DNA Methylation Signature as an Independent Prognostic Factor in Muscle-Invasive Bladder Cancer.

Background: Muscle-invasive bladder cancer (MIBC) accounts for approximately 20% of all urothelial bladder carcinomas (UBC) at time of diagnosis, and up to 30% of patients with non-muscle invasive UBC will progress to MIBC over time. An increasing body of evidence has revealed a strong correlation between aberrant DNA methylation and tumorigenesis in MIBC.

Results: Using The Cancer Genome Atlas (TCGA) molecular data for 413 patients, we described a DNA methylation-based signature as a prognostic factor for overall survival (OS) in MIBC patients.

The genome-wide impact of trisomy 21 on DNA methylation and its implications for hematopoiesis.

Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10) and 1,052 differentially methylated regions.

: a web application to identify the most similar mutational signature using shiny.

There are two frameworks for characterizing mutational signatures which are commonly used to describe the nucleotide patterns that arise from mutational processes. Estimated mutational signatures from fitting these two methods in human cancer can be found online, in the Catalogue Of Somatic Mutations In Cancer (COSMIC) website or a GitHub repository. The two frameworks make differing assumptions regarding independence of base pairs and for that reason may produce different results.

DNA Methylation Profiles of Vegans and Non-Vegetarians in the Adventist Health Study-2 Cohort.

We sought to determine if DNA methylation patterns differed between vegans and non-vegetarians in the Adventist Health Study-2 cohort. Genome-wide DNA methylation derived from buffy coat was profiled in 62 vegans and 142 non-vegetarians. Using linear regression, methylation of CpG sites and genes was categorized or summarized according to various genic/intergenic regions and CpG island-related regions, as well as the promoter.

Epigenetic Conservation Is a Beacon of Function: An Analysis Using Methcon5 Software for Studying Gene Methylation.

Purpose: Different epigenetic configurations allow one genome to develop into multiple cell types. Although the rules governing what epigenetic features confer gene expression are increasingly being understood, much remains uncertain. Here, we used a novel software package, Methcon5, to explore whether the principle of biologic conservation can be used to identify expressed genes.

Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype.

Highly tumorigenic, drug-resistant cancer stem-like cells drive cancer progression. These aggressive cells can arise repeatedly from bulk tumor cells independently of mutational events, suggesting an epigenetic mechanism. To test this possibility, we studied bladder cancer cells as they cyclically shifted to and from a cancer stem-like phenotype, and we discovered that these two states exhibit distinct DNA methylation and chromatin accessibility.

Mutational signatures in colon cancer.

Objective: Recently, many tumor sequencing studies have inferred and reported on mutational signatures, short nucleotide patterns at which particular somatic base substitutions appear more often. A number of signatures reflect biological processes in the patient and factors associated with cancer risk. Our goal is to infer mutational signatures appearing in colon cancer, a cancer for which environmental risk factors vary by cancer subtype, and compare the signatures to those in adult stem cells from normal colon.

Systematic Review and Meta-analysis of Testicular Germ Cell Tumors Following In Utero Exposure to Diethylstilbestrol.

Background: Early exposure to estrogen-like compounds has been implicated in the etiology of testicular cancer, but individual level epidemiologic data addressing this hypothesis are scarce. The synthetic estrogen diethylstilbestrol (DES) was administered during pregnancy from 1948 to 1971, but sequelae of in utero exposure have been more extensively characterized in females than in males.

Methods: By systematic review, we sought to identify all epidemiologic research relating testicular cancer to a history of in utero exposure to diethylstilbestrol.

HiLDA: a statistical approach to investigate differences in mutational signatures.

We propose a hierarchical latent Dirichlet allocation model (HiLDA) for characterizing somatic mutation data in cancer. The method allows us to infer mutational patterns and their relative frequencies in a set of tumor mutational catalogs and to compare the estimated frequencies between tumor sets. We apply our method to two datasets, one containing somatic mutations in colon cancer by the time of occurrence, before or after tumor initiation, and the second containing somatic mutations in esophageal cancer by sex, age, smoking status, and tumor site.

Epigenetic Heterogeneity in Human Colorectal Tumors Reveals Preferential Conservation And Evidence of Immune Surveillance.

Genomic intratumoral heterogeneity (ITH) is common in cancers, but the extent of phenotypic ITH is uncertain because most subclonal mutations are passengers. Since tumor phenotypes are largely driven by epigenetics, methylomic analyses can provide insights into phenotypic ITH. Following this principle, we determined the extent of epigenetic ITH in 16 human colorectal tumors by comparing the methylomes from spatially separated regions in each tumor.

Data integration by multi-tuning parameter elastic net regression.

Background: To integrate molecular features from multiple high-throughput platforms in prediction, a regression model that penalizes features from all platforms equally is commonly used. However, data from different platforms are likely to differ in effect sizes, the proportion of predictive features, and correlations structures. Subtle but important features may be missed by shrinking all features equally.

Association between promoter methylation and lung function growth during adolescence.

is one of the TAM ( and ) receptor tyrosine kinases and may be involved in airway inflammation. Little is known about how epigenetic changes in may affect lung development during adolescence. We investigated the association between DNA methylation at birth and lung function growth from 10 to 18 years of age in 923 subjects from the Children's Health Study (CHS).

Association of internal smoking dose with blood DNA methylation in three racial/ethnic populations.

Background: Lung cancer is the leading cause of cancer-related death. While cigarette smoking is the primary cause of this malignancy, risk differs across racial/ethnic groups. For the same number of cigarettes smoked, Native Hawaiians compared to whites are at greater risk and Japanese Americans are at lower risk of developing lung cancer.

Self-reported prenatal tobacco smoke exposure, AXL gene-body methylation, and childhood asthma phenotypes.

Background: Epigenetic modifications, including DNA methylation, act as one potential mechanism underlying the detrimental effects associated with prenatal tobacco smoke (PTS) exposure. Methylation in a gene called AXL was previously reported to differ in response to PTS.

Methods: We investigated the association between PTS and epigenetic changes in AXL and how this was related to childhood asthma phenotypes.

Spatial mutation patterns as markers of early colorectal tumor cell mobility.

A growing body of evidence suggests that a subset of human cancers grows as single clonal expansions. In such a nearly neutral evolution scenario, it is possible to infer the early ancestral tree of a full-grown tumor. We hypothesized that early tree reconstruction can provide insights into the mobility phenotypes of tumor cells during their first few cell divisions.