‘Longing’ for the Next Generation of Liquid Biopsy: The Diagnostic Potential of Long Cell-Free DNA in Oncology and Prenatal Testing

Yu, Stephanie C Y; Choy, L Y Lois; Lo, Y.M. Dennis

doi:10.1007/s40291-023-00661-2

Cited by 4 publications

(1 citation statement)

References 33 publications

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“…Single-molecule sequencing technologies, including Pacific Biosciences (PacBio) single-molecule real-time (SMRT) sequencing and Oxford Nanopore Technologies (ONT) sequencing, have opened up the possibility of detecting and characterizing long cfDNA molecules. Recent studies using these platforms have uncovered a population of long cfDNA molecules, up to tens of kilobases, in the plasma DNA of healthy, pregnant individuals and patients with cancer ( Yu et al 2021 , 2023a ,b; Choy et al 2022 ). Depending on the sequencing platforms used, long molecules account for about a median of 15% and 5% of the total molecules from SMRT and ONT platforms, respectively ( Yu et al 2023b ).…”

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Genomic origin, fragmentomics, and transcriptional properties of long cell-free DNA molecules in human plasma

Che,

Jiang,

Choy

et al. 2024

Genome Res.

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Recent studies have revealed an unexplored population of long cell-free DNA (cfDNA) molecules in human plasma using long-read sequencing technologies. However, the biological properties of long cfDNA molecules (> 500 bp) remain largely unknown. To this end, we investigated the origins of long cfDNA molecules from different genomic elements. Analysis of plasma cfDNA using long-read sequencing revealed uneven distribution of long molecules from across the genome. Long cfDNA molecules showed overrepresentation in euchromatic regions of the genome, in sharp contrast to short DNA molecules. We observed a stronger relationship between the abundance of long molecules and mRNA gene expression levels, compared with short molecules (Pearson's r = 0.71 versus -0.14). Moreover, long and short molecules demonstrated distinct fragmentation patterns surrounding CpG sites. Leveraging the cleavage preferences surrounding CpG sites, the combined cleavage ratios of long and short molecules could differentiate patients with hepatocellular carcinoma (HCC) from non-HCC subjects (AUC = 0.87). We further investigated knockout mice in which selected nuclease genes had been inactivated, in comparison with wild-type mice. The proportion of long molecules originating from transcription start sites were lower inDffb-deficient mice but higher inDnase1l3-deficient mice, compared to that of wild-type mice. This work thus provides new insights into the biological properties and potential clinical applications of long cfDNA molecules.

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confidence: 99%

Genomic origin, fragmentomics, and transcriptional properties of long cell-free DNA molecules in human plasma

Che,

Jiang,

Choy

et al. 2024

Genome Res.

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

Hou,

Meng,

Zhou

2024

Advanced Science

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

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Fragle: Universal ctDNA quantification using deep learning of fragmentomic profiles

Zhu,

Rahman,

Getty

et al. 2023

Preprint

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Quantification of circulating tumor DNA (ctDNA) in blood enables non-invasive surveillance of cancer progression. Fragle is a fast deep learning-based method for estimation of ctDNA levels directly from cell-free DNA fragment length profiles. Fragle accurately estimates ctDNA levels across different cancer types from both low-pass whole genome and targeted sequencing data, enabling uniform quantification of blood ctDNA levels across sequencing assays and cancer patients.

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‘Longing’ for the Next Generation of Liquid Biopsy: The Diagnostic Potential of Long Cell-Free DNA in Oncology and Prenatal Testing

Cited by 4 publications

References 33 publications

Genomic origin, fragmentomics, and transcriptional properties of long cell-free DNA molecules in human plasma

Genomic origin, fragmentomics, and transcriptional properties of long cell-free DNA molecules in human plasma

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

Fragle: Universal ctDNA quantification using deep learning of fragmentomic profiles

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