Whole-genome bisulfite sequencing of cell-free DNA unveils age-dependent and ALS-associated methylation alterations

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

Abstract Background Cell-free DNA (cfDNA) in plasma carries epigenetic signatures specific to tissue or cell of origin. Aberrant methylation patterns circulating cfDNA have emerged as valuable tools for noninvasive cancer detection, prenatal diagnostics, and organ transplant assessment. Such changes also hold significant promise the diagnosis neurodegenerative diseases, which often progresses slowly has a lengthy asymptomatic period. However, genome-wide diseases remain poorly understood. Results We used whole-genome bisulfite sequencing (WGBS) profile age-dependent ALS-associated from 30 individuals, including young middle-aged controls, well ALS patients with matched controls. identified 5,223 age-related differentially methylated loci (DMLs) (FDR < 0.05), 51.6% showing hypomethylation older individuals. Our results significantly overlapped age-associated CpGs large blood-based epigenome-wide association study (EWAS). Comparing we detected 1,045 regions (DMRs) gene bodies, promoters, intergenic regions. Notably, these DMRs were linked key pathways, endocytosis adhesion. Integration spinal cord transcriptomics revealed that 31% DMR-associated genes exhibited differential expression compared over 20 correlating disease duration. Furthermore, comparison published single-nucleus RNA (snRNA-Seq) data demonstrated reflects cell-type-specific dysregulation brain patients, particularly excitatory neurons astrocytes. Deconvolution profiles suggested altered proportions immune liver-derived patients. Conclusions is powerful tool assessing ALS-specific molecular by revealing perturbed locus, genes, proportional contributions different tissues/cells plasma. This technique holds clinical application biomarker discovery across broad spectrum disorders.

Language: Английский

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5-Hydroxymethylcytosine modifications in circulating cell-free DNA: frontiers of cancer detection, monitoring, and prognostic evaluation

Biomarker Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 7, 2025

Abstract Developing accurate, clinically convenient, and non-invasive methods for early cancer detection, monitoring, prognosis assessment is essential improving patient survival rates, enhancing quality of life, reducing the socioeconomic burden associated with cancer. This goal critical in precision oncology. Genetic epigenetic alterations circulating cell-free DNA (cfDNA) have emerged as transformative tools advancing outcomes. Among these, 5-hydroxymethylcytosine (5hmC) modifications cfDNA stand out promising markers, offering insights into initiation, progression, metastasis, across various types, such lung cancer, colorectal hepatocellular carcinoma. review comprehensively explores biology sequencing methodologies 5hmC, emphasizing their potential screening, diagnosis, treatment prognostic assessment. It highlights recent advancements cfDNA-derived 5hmC signatures’ applications, addressing strengths limitations context clinical translation. Furthermore, this outlines key challenges future directions integrating routine practice, facilitating personalized management.

Language: Английский

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Telomere Length Changes in Cancer: Insights on Carcinogenesis and Potential for Non-Invasive Diagnostic Strategies

Genes, Journal Year: 2023, Volume and Issue: 14(3), P. 715 - 715

Published: March 14, 2023

Telomere dynamics play a crucial role in the maintenance of chromosome integrity; changes telomere length may thus contribute to development various diseases including cancer. Understanding telomeric DNA carcinogenesis and detecting presence cell-free (cf-telDNA) body fluids offer potential biomarker for novel cancer screening diagnostic strategies. Liquid biopsy is becoming increasingly popular due its undeniable benefits over conventional invasive methods. However, organization function cf-telDNA extracellular milieu are understudied. This paper provides review based on 3,398,017 patients, patients with other conditions, control individuals aim shed more light inconsistent nature lengthening/shortening oncological contexts. To gain better understanding biological factors (e.g., telomerase activation, alternative lengthening telomeres) affecting homeostasis across different types cancer, we summarize mechanisms responsible maintenance. In conclusion, compare tissue- liquid biopsy-based approaches assessment provide brief outlook methodology used evaluation, highlighting advances state-of-the-art field.

Language: Английский

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Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

eLife, Journal Year: 2023, Volume and Issue: 12

Published: July 25, 2023

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published date demanded a very high-depth sequencing, resulting an elevated price test. Herein, we developed multimodal assay called SPOT-MAS (screening presence by methylation size) simultaneously profile methylomics, fragmentomics, copy number, end motifs single workflow using targeted shallow genome-wide sequencing (~0.55×) cell-free DNA. We applied 738 non-metastatic patients with breast, colorectal, gastric, lung, liver cancer, 1550 healthy controls. then employed machine learning extract multiple cancer tissue-specific signatures detecting locating cancer. successfully detected five types sensitivity 72.4% at 97.0% specificity. The sensitivities early-stage cancers were 73.9% 62.3% stages I II, respectively, increasing 88.3% stage IIIA. For tumor-of-origin, our achieved accuracy 0.7. Our study demonstrates comparable performance other ctDNA-based while requiring significantly lower depth, making it economically feasible population-wide screening.

Language: Английский

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Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Oct. 11, 2023

Despite their promise, circulating tumor DNA (ctDNA)-based assays for multi-cancer early detection face challenges in test performance, due mostly to the limited abundance of ctDNA and its inherent variability. To address these challenges, published date demanded a very high-depth sequencing, resulting an elevated price test. Herein, we developed multimodal assay called SPOT-MAS (screening presence by methylation size) simultaneously profile methylomics, fragmentomics, copy number, end motifs single workflow using targeted shallow genome-wide sequencing (~0.55×) cell-free DNA. We applied 738 non-metastatic patients with breast, colorectal, gastric, lung, liver cancer, 1550 healthy controls. then employed machine learning extract multiple cancer tissue-specific signatures detecting locating cancer. successfully detected five types sensitivity 72.4% at 97.0% specificity. The sensitivities early-stage cancers were 73.9% 62.3% stages I II, respectively, increasing 88.3% stage IIIA. For tumor-of-origin, our achieved accuracy 0.7. Our study demonstrates comparable performance other ctDNA-based while requiring significantly lower depth, making it economically feasible population-wide screening.

Language: Английский

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Cell-Free DNA As Peripheral Biomarker of Alzheimer’s Disease

Aging and Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Alzheimer's disease (AD) and disease-related disorders (ADRD) are progressive neurodegenerative diseases without cure. occurs in 2 forms, early-onset familial AD late-onset sporadic AD. Early-onset is a rare (~1%), autosomal dominant, caused by mutations presenilin-1, presenilin-2, amyloid precursor protein genes the other late-onset, prevalent evolved due to age-associated complex interactions between environmental genetic factors, addition apolipoprotein E4 polymorphism. Cellular senescence, promoting impairment of physical mental functions constituted be main cause aging, primary risk factor for AD, which results loss cognitive function, memory, visual-spatial skills an individual live or act independently. Despite significant progress understanding biology pathophysiology we continue lack definitive early detectable biomarkers and/or drug targets that can used delay development ADRD elderly populations. However, recent developments studies DNA double-strand breaks result release fragmented into bloodstream contribute higher levels cell-free (cf-DNA). This cf-DNA released from various cell types, including normal cells undergoing apoptosis necrosis elevated blood have potential serve as blood-based biomarker detection ADRD. The overall goal our study discuss latest circulating progression Our article summarized status research on both healthy states how these develop also discussed impact lifestyle epigenetic factors involved

Language: Английский

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Plasma cfDNA methylation markers for the detection and prognosis of ovarian cancer

EBioMedicine, Journal Year: 2022, Volume and Issue: 83, P. 104222 - 104222

Published: Aug. 13, 2022

Language: Английский

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Liquid biopsy in hematological malignancies: current and future applications

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: April 20, 2023

The assessment of the cancer mutational profile is crucial for patient management, stratification, and therapeutic decisions. At present, in hematological malignancies with a solid mass, such as lymphomas, tumor genomic profiling generally performed on tissue biopsy, but may harbor genetic lesions that are unique to other anatomical compartments. analysis circulating DNA (ctDNA) liquid biopsy an emerging approach allows genotyping monitoring disease during therapy follow-up. This review presents different methods ctDNA describes application malignancies. In diffuse large B-cell lymphoma (DLBCL) Hodgkin (HL), recapitulates can identify mutations otherwise absent biopsy. addition, changes amount after one or two courses chemotherapy significantly predict outcomes. has also been tested myeloid neoplasms promising results. addition analysis, carries potential future applications ctDNA, including fragmentation epigenetic patterns. On these grounds, several clinical trials aiming at incorporating treatment tailoring currently ongoing

Language: Английский

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The Hippo signaling pathway in gastric cancer

Acta Biochimica et Biophysica Sinica, Journal Year: 2023, Volume and Issue: unknown

Published: March 1, 2023

Gastric cancer (GC) is an aggressive malignant disease which still lacks effective early diagnosis markers and targeted therapies, representing the fourth-leading cause of cancer-associated death worldwide. The Hippo signaling pathway plays crucial roles in organ size control tissue homeostasis under physiological conditions, yet its aberrations have been closely associated with several hallmarks cancer. last decade witnessed a burst investigations dissecting how dysregulation contributes to tumorigenesis, highlighting therapeutic potential targeting this for tumor intervention. In review, we systemically document studies on contexts gastric initiation, progression, metastasis, acquired drug resistance, emerging development Hippo-targeting strategies. By summarizing major open questions field, aim inspire further in-depth understanding GC development, as well translational implications treatment.

Language: Английский

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Application and development of noninvasive biomarkers for colorectal cancer screening: a systematic review

International Journal of Surgery, Journal Year: 2023, Volume and Issue: 109(4), P. 925 - 935

Published: March 28, 2023

Background: Colorectal cancer (CRC) is the second most common cause of cancer-related death (9.4% 9.9 million deaths). However, CRC develops slowly, and early detection intervention can effectively improve survival rate quality life. Although colonoscopy detect diagnose CRC, it unsuitable for screening in average-risk populations. Some commercial kits based on DNA mutation or methylation are approved screening, but low sensitivity advanced adenoma early-stage would limit applications. Main results: Recently, researchers have focused developing noninvasive minimally invasive, easily accessible biomarkers with higher accuracy screening. Numerous reports describe advances biomarkers, including mutations methylation, mRNA miRNA, gut microbes, metabolites, as well low-throughput multiomics panels. In small cohorts, specificity improved when fecal immunochemical testing combined other biomarkers; further verification large cohorts expected. addition, continuous improvement laboratory technology has also technology, such PCR, application CRISPR/Cas technology. Besides, artificial intelligence extensively promoted mining biomarkers. Machine learning was performed to construct a diagnosis model cfDNA fragment features from whole-genome sequencing data. another study, markers, cfDNA, epigenetic, protein signals, were discovered by machine learning. Finally, advancements sensor promote applicability volatile organic compounds detection. Conclusion: Here, authors review different biomarker types. Most studies reported optimistic findings preliminary research, prospective clinical ongoing. These promising expected more accurately identify patients be applied future.

Language: Английский

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