Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(2), P. 225 - 237.e5

Published: Jan. 25, 2024

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given known epigenetic regulation critical SCLC programs, we hypothesized that subtype-specific patterns DNA methylation could be detected tumor or blood from patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) two cohorts totaling 179 patients and using machine learning approaches, report a highly accurate methylation-based classifier (SCLC-DMC) can distinguish subtypes. We further adjust for circulating-free (cfDNA) subtype plasma. cfDNA (cfDMC), demonstrate phenotypes evolve during disease progression, highlighting need longitudinal tracking clinical treatment. These data establish used identify subtypes might guide precision therapy.

Language: Английский

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Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or lines. Here, we utilize single transcriptome data as comprehensive cellular reference set disease-agnostic cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression rank relative contribution over 490 plasma cfDNA. In 744 healthy individuals and patients, uncover type signatures support emerging paradigms oncology prenatal care. train predictive models can differentiate patients colorectal cancer (84.7%), early-stage breast (90.1%), multiple myeloma (AUC 95.0%), preeclampsia (88.3%) from matched controls. Importantly, our approach performs well ultra-low coverage datasets be readily transferred diverse clinical settings expansion liquid biopsy.

Language: Английский

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Liquid Biopsy Based on Cell-Free DNA and RNA

Annual Review of Biomedical Engineering, Journal Year: 2024, Volume and Issue: 26(1), P. 169 - 195

Published: Feb. 12, 2024

This review delves into the rapidly evolving landscape of liquid biopsy technologies based on cell-free DNA (cfDNA) and RNA (cfRNA) their increasingly prominent role in precision medicine. With advent high-throughput sequencing, use cfDNA cfRNA has revolutionized noninvasive clinical testing. Here, we explore physical characteristics cfRNA, present an overview essential engineering tools used by field, highlight applications, including prenatal testing, cancer organ transplantation surveillance, infectious disease Finally, discuss emerging broadening scope biopsies to new areas diagnostic

Language: Английский

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Circulating tumor DNA in B-cell lymphoma: technical advances, clinical applications, and perspectives for translational research

Leukemia, Journal Year: 2022, Volume and Issue: 36(9), P. 2151 - 2164

Published: June 14, 2022

Abstract Noninvasive disease monitoring and risk stratification by circulating tumor DNA (ctDNA) profiling has become a potential novel strategy for patient management in B-cell lymphoma. Emerging innovative therapeutic options an unprecedented growth our understanding of biological molecular factors underlying lymphoma heterogeneity have fundamentally increased the need precision-based tools facilitating personalized accurate quantification. By capturing entire mutational landscape tumors, ctDNA assessment some decisive advantages over conventional tissue biopsies, which usually target only one single site. Due to its non- or minimal-invasive nature, serial repeated provides real-time picture genetic composition facilitates quantification burden any time during course disease. In this review, we present comprehensive overview technologies used detection genotyping lymphoma, focusing on pre-analytical technical requirements, limitations various approaches, highlight recent advances around improving sensitivity suppressing errors. We broadly review applications clinical practice translational research describing how might enhance subtype classification, treatment response assessment, outcome prediction, measurable residual finally discuss could be implemented prospective trials as surrogate endpoint utilized decision-making tool guide future.

Language: Английский

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New Perspectives on the Importance of Cell-Free DNA Biology

Diagnostics, Journal Year: 2022, Volume and Issue: 12(9), P. 2147 - 2147

Published: Sept. 3, 2022

Body fluids are constantly replenished with a population of genetically diverse cell-free DNA (cfDNA) fragments, representing vast reservoir information reflecting real-time changes in the host and metagenome. As many body can be collected non-invasively one-off serial fashion, this tapped to develop assays for diagnosis, prognosis, monitoring wide-ranging pathologies, such as solid tumors, fetal genetic abnormalities, rejected organ transplants, infections, potentially others. The translation cfDNA research into useful clinical tests is gaining momentum, recent progress being driven by rapidly evolving preanalytical analytical procedures, integrated bioinformatics, machine learning algorithms. Yet, despite these spectacular advances, remains very challenging analyte due its immense heterogeneity fluctuation vivo. It increasingly recognized that high-fidelity reconstruction stored cfDNA, turn development fit roll-out, requires much deeper understanding both physico-chemical features biological, physiological, lifestyle, environmental factors modulate it. This daunting task, but significant upsides. In review we showed how expanded knowledge on biology faithful reverse-engineering samples promises (i) augment sensitivity specificity existing assays; (ii) expand repertoire disease-specific markers, thereby leading powerful (iii) reshape personal molecular medicine; (iv) have an unprecedented impact genetics research.

Language: Английский

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Fragmentomic analysis of circulating tumor DNA-targeted cancer panels

Annals of Oncology, Journal Year: 2023, Volume and Issue: 34(9), P. 813 - 825

Published: June 16, 2023

Language: Английский

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Integrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 24, 2023

Abstract High grade serous ovarian carcinoma (HGSOC) is a highly heterogeneous disease that typically presents at an advanced, metastatic state. The multi-scale complexity of HGSOC major obstacle to predicting response neoadjuvant chemotherapy (NACT) and understanding critical determinants response. Here we present framework predict the patients NACT integrating baseline clinical, blood-based, radiomic biomarkers extracted from all primary lesions. We use ensemble machine learning model trained change in total volume using data obtained diagnosis ( n = 72). validated internal hold-out cohort 20) independent external patient 42). In integrated radiomics reduces prediction error by 8% with respect clinical model, achieving AUC 0.78 for RECIST 1.1 classification compared 0.47 model. Our results emphasize value including integrative models treatment provide methods developing new biomarker-based trials HGSOC.

Language: Английский

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The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection

Genome biology, Journal Year: 2023, Volume and Issue: 24(1)

Published: Oct. 12, 2023

Abstract Background Existing methods to detect tumor signal in liquid biopsy have focused on the analysis of nuclear cell-free DNA (cfDNA). However, non-nuclear cfDNA and particular mitochondrial (mtDNA) has been understudied. We hypothesize that an increase mtDNA plasma could reflect presence cancer, leveraging enhance cancer detection. Results survey 203 healthy 664 samples from three collection centers covering 12 types with whole genome sequencing catalogue fraction. The fraction is increased individuals cholangiocarcinoma, colorectal, liver, pancreatic, or prostate comparison individuals. almost no other types. correlates as determined by somatic mutations and/or copy number aberrations. also elevated a patients without apparent tumor-derived cfDNA. A predictive model integrating increases area under curve (AUC) 0.73 when using alterations alone AUC 0.81. Conclusions retrieved potential boost detection combined signals biopsies.

Language: Английский

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Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions

Science Advances, Journal Year: 2024, Volume and Issue: 10(15)

Published: April 10, 2024

We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) small cell lung (SCLC). In SCLC, differential activation transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. designed a capture panel that identifies chromatin organization signatures at 1535 TF binding sites 13,240 gene start detects exonic mutations in 842 genes. Sequencing cfDNA from SCLC patient-derived xenograft models captured activity expression revealed individual highly informative loci. Prediction ASCL1 NEUROD1 using loci achieved areas under the receiver operating characteristic curve (AUCs) 0.84 to 0.88 patients with SCLC. As non-SCLC (NSCLC) often transforms following therapy, we applied our framework distinguish NSCLC AUC 0.99. Our shows promising utility subtyping transformation monitoring, potential applicability diverse tumor types.

Language: Английский

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Systematically Evaluating Cell‐Free DNA Fragmentation Patterns for Cancer Diagnosis and Enhanced Cancer Detection via Integrating Multiple Fragmentation Patterns

Advanced Science, Journal Year: 2024, Volume and Issue: 11(30)

Published: June 17, 2024

Cell-free DNA (cfDNA) fragmentation patterns have immense potential for early cancer detection. However, the definition of varies, ranging from entire genome to specific genomic regions. These not been systematically compared, impeding broader research and practical implementation. Here, 1382 plasma cfDNA sequencing samples 8 types are collected. Considering that within open chromatin regions is more susceptible fragmentation, 10 as features employed machine learning techniques evaluate their performance examined. All demonstrated discernible classification capabilities, with end motif showing highest diagnostic value cross-validation. Combining cross independent validation results revealed incorporated both fragment length coverage information exhibited robust predictive capacities. Despite potential, power these unstable. To address this limitation, an ensemble classifier via integrating all developed, which notable improvements in detection tissue-of-origin determination. Further functional bioinformatics investigations on significant feature intervals model its impressive ability identify critical regulatory involved pathogenesis.

Language: Английский

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