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One epigenetic hallmark of many cancer types is differential DNA methylation occurring at multiple loci compared to normal tissue. Detection and assessment of the methylation state at a specific locus could be an effective cancer diagnostic. We assessed the effectiveness of hypermethylation at the CpG island of ZNF154, a previously reported multi-cancer specific signature for use in a blood-based cancer detection assay. To predict its effectiveness, we compared methylation levels of 3698 primary tumors encompassing 11 solid cancers, 724 controls, 2711 peripheral blood cell samples, and 350 noncancer disease tissues from publicly available methylation array datasets. We performed a single-molecule high-resolution DNA melt analysis on 71 plasma samples from cancer patients and 20 noncancer individuals to assess ZNF154 methylation as a candidate diagnostic metric in liquid biopsy and compared results to KRAS mutation frequency in the case of pancreatic carcinoma. We documented ZNF154 hypermethylation in early stage tumors, which did not increase in most noncancer disease or with respect to age or sex in peripheral blood cells, suggesting it is a promising target in liquid biopsy. ZNF154 cfDNA methylation discriminated cases from healthy donor plasma samples in minimal plasma volumes and outperformed KRAS mutation frequency in pancreatic cancer.

Background: Meiosis is a specialized germ cell cycle that generates haploid gametes. In the initial stage of meiosis, meiotic prophase I (MPI), homologous chromosomes pair and recombine. Extensive changes in chromatin in MPI raise an important question concerning the contribution of epigenetic mechanisms such as DNA methylation to meiosis. Interestingly, previous studies concluded that in male mice, genome-wide DNA methylation patters are set in place prior to meiosis and remain constant subsequently. However, no prior studies examined DNA methylation during MPI in a systematic manner necessitating its further investigation., Results: In this study, we used genome-wide bisulfite sequencing to determine DNA methylation of adult mouse spermatocytes at all MPI substages, spermatogonia and haploid sperm. This analysis uncovered transient reduction of DNA methylation (TRDM) of spermatocyte genomes. The genome-wide scope of TRDM, its onset in the meiotic S phase and presence of hemimethylated DNA in MPI are all consistent with a DNA replication-dependent DNA demethylation. Following DNA replication, spermatocytes regain DNA methylation gradually but unevenly, suggesting that key MPI events occur in the context of hemimethylated genome. TRDM also uncovers the prior deficit of DNA methylation of LINE-1 retrotransposons in spermatogonia resulting in their full demethylation during TRDM and likely contributing to the observed mRNA and protein expression of some LINE-1 elements in early MPI., Conclusions: Our results suggest that contrary to the prevailing view, chromosomes exhibit dynamic changes in DNA methylation in MPI. We propose that TRDM facilitates meiotic prophase processes and gamete quality control.

Epigenetic dysregulation is recognized as a hallmark of cancer. In the last 16 years, a CpG island methylator phenotype (CIMP) has been documented in tumors originating from different tissues. However, a looming question in the field is whether or not CIMP is a pan-cancer phenomenon or a tissue-specific event. Here, we give a synopsis of the history of CIMP and describe the pattern of DNA methylation that defines the CIMP phenotype in different cancer types. We highlight new conceptual approaches of classifying tumors based on CIMP in a cancer type-agnostic way that reveal the presence of distinct CIMP tumors in a multitude of The Cancer Genome Atlas (TCGA) datasets, suggesting that this phenotype may transcend tissue-type specificity. Lastly, we show evidence supporting the clinical relevance of CIMP-positive tumors and suggest that a common CIMP etiology may define new mechanistic targets in cancer treatment., Competing Interests: The authors declare no conflict of interest.

Simple Summary: Tumors are known to shed DNA into the bloodstream, and since the tumor DNA is marked by aberrant methylation patterns, this can be exploited for their detection through a simple blood sample. However, specific methylation biomarkers that efficiently detect a broad range of tumors and are effective at early-stage disease are still lacking. In this study we identify two novel methylation biomarkers and combine these with an already existing biomarker to improve multi-cancer detection. We test their performances as individual and combined markers using large methylation array datasets covering multiple cancer types, mimic blood samples using data from healthy blood cell DNA, and finally test the biomarkers in cancer plasma samples. We find that the combination of markers greatly improves the ability of the test to distinguish between cancer and normal samples, and in addition we provide the research field with a complete workflow for evaluating novel methylation biomarkers based on pre-existing datasets. The ability to detect several types of cancer using a non-invasive, blood-based test holds the potential to revolutionize oncology screening. We mined tumor methylation array data from the Cancer Genome Atlas (TCGA) covering 14 cancer types and identified two novel, broadly-occurring methylation markers at TLX1 and GALR1. To evaluate their performance as a generalized blood-based screening approach, along with our previously reported methylation biomarker, ZNF154, we rigorously assessed each marker individually or combined. Utilizing TCGA methylation data and applying logistic regression models within each individual cancer type, we found that the three-marker combination significantly increased the average area under the ROC curve (AUC) across the 14 tumor types compared to single markers (p = 1.158 × 10−10; Friedman test). Furthermore, we simulated dilutions of tumor DNA into healthy blood cell DNA and demonstrated increased AUC of combined markers across all dilution levels. Finally, we evaluated assay performance in bisulfite sequenced DNA from patient tumors and plasma, including early-stage samples. When combining all three markers, the assay correctly identified nine out of nine lung cancer plasma samples. In patient plasma from hepatocellular carcinoma, ZNF154 alone yielded the highest combined sensitivity and specificity values averaging 68% and 72%, whereas multiple markers could achieve higher sensitivity or specificity, but not both. Altogether, this study presents a comprehensive pipeline for the identification, testing, and validation of multi-cancer methylation biomarkers with a considerable potential for detecting a broad range of cancer types in patient blood samples. [ABSTRACT FROM AUTHOR]

This study aimed to assess (1) blood pressure between young, current athletes, and non‐athletes early in life; (2) hypertension prevalence between former athletes and the general population later in life; and (3) understand the mechanisms between exercise training and hypertension risks in the form of DNA methylation. Study 1: A total of 354 young male participants, including current athletes, underwent blood pressure assessment. Study 2: The prevalence of hypertension in 1269 male former athletes was compared with that in the Japanese general population. Current and former athletes were divided into three groups: endurance‐, mixed‐, and sprint/power‐group. Study 3: We analyzed the effect of aerobic‐ or resistance‐training on DNA methylation patterns using publicly available datasets to explore the possible underlying mechanisms. In young, current athletes, the mixed‐ and sprint/power‐group exhibited higher systolic blood pressure, and all groups exhibited higher pulse pressure than non‐athletes. In contrast, the prevalence of hypertension in former athletes was significantly lower in all groups than in the general population. Compared to endurance‐group (reference), adjusted‐hazard ratios for the incidence of hypertension among mixed‐ and sprint/power‐group were 1.24 (0.87–1.84) and 1.50 (1.04–2.23), respectively. Moreover, aerobic‐ and resistance‐training commonly modified over 3000 DNA methylation sites in skeletal muscle, and these were suggested to be associated with cardiovascular function‐related pathways. These findings suggest that the high blood pressure induced by exercise training at a young age does not influence the development of future hypertension. Furthermore, previous exercise training experiences at a young age could decrease the risk of future hypertension. [ABSTRACT FROM AUTHOR]