Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma

Jiang, Peiyong; Sun, Kun; Yu, Tong; Cheng, Suk Hang; Cheng, Timothy H.T.; Heung, Macy M. S.; Wong, John; Wong, Vincent Wai‐Sun; Chan, Henry Lik‐Yuen; Chan, Ka‐Kui; Lo, Y.M. Dennis; Chiu, Rossa W.̉K.

doi:10.1073/pnas.1814616115

Cited by 173 publications

(175 citation statements)

References 26 publications

(65 reference statements)

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“…In pregnancy, fetal-derived plasma DNA (mainly of placental origin) were observed to be linear fragments of DNA that were shorter than the maternal-derived (mainly of hematopoietic origin) DNA (1,5,6). In cancer, tumor-derived cfDNA were detected with smaller sizes and preferred end coordinates from those derived from nonmalignant cells (7)(8)(9). Diagnostic applications had been demonstrated for using the fragmentation patterns of plasma DNA in noninvasive prenatal testing and cancer testing (5,6,(10)(11)(12).…”

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confidence: 99%

Identification and characterization of extrachromosomal circular DNA in maternal plasma

Sin

Jiang

Deng

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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We explored the presence of extrachromosomal circular DNA (eccDNA) in the plasma of pregnant women. Through sequencing following either restriction enzyme or Tn5 transposase treatment, we identified eccDNA molecules in the plasma of pregnant women. These eccDNA molecules showed bimodal size distributions peaking at ∼202 and ∼338 bp with distinct 10-bp periodicity observed throughout the size ranges within both peaks, suggestive of their nucleosomal origin. Also, the predominance of the 338-bp peak of eccDNA indicated that eccDNA had a larger size distribution than linear DNA in human plasma. Moreover, eccDNA of fetal origin were shorter than the maternal eccDNA. Genomic annotation of the overall population of eccDNA molecules revealed a preference of these molecules to be generated from 5′-untranslated regions (5′-UTRs), exonic regions, and CpG island regions. Two sets of trinucleotide repeat motifs flanking the junctional sites of eccDNA supported multiple possible models for eccDNA generation. This work highlights the topologic analysis of plasma DNA, which is an emerging direction for circulating nucleic acid research and applications.

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confidence: 99%

Identification and characterization of extrachromosomal circular DNA in maternal plasma

Sin

Jiang

Deng

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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140

173

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“…This study provides a new pipeline for finding new molecular markers for cancers from cfDNA by combining SALP-seq and machine learning. In recent years, as a good material for cancer liquid biopsy, plasma cfDNA has been widely analyzed by next generation sequencing (NGS) for finding new molecular markers for cancer diagnosis such as fragment size 43,44 , methylation [45][46][47] , and end coordinate 48,49 . However, the size-based plasma DNA diagnostics still faced some limitations that may challenge its wide application 50 .…”

Section: Discussionmentioning

confidence: 99%

Finding new cancer epigenetic and genetic biomarkers from cell-free DNA by combining SALP-seq and machine learning: esophageal cancer as an example

Liu

Xia

et al. 2020

Preprint

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Background: Cancer is an important public health problem worldwide and its early diagnosis and effective prognosis are critical for its treatment. In recent years, as a good material for cancer liquid biopsy, plasma cell-free DNA (cfDNA) has been widely analyzed by next generation sequencing (NGS) for finding new molecular markers for cancer diagnosis such as size, methylation and end coordinate. However, the current studies did not still involve esophageal cancer (ESCA), a main cancer that seriously threatens human health and life in China. Here we therefore tried to find new biomarkers for this cancer from cfDNA. Materials & methods: Thirty cfDNA samples from 26 ESCA patients and 4 healthy people were used to construct the NGS libraries and sequenced by using SALP-seq. The sequencing data were analyzed with variant bioinformatics methods for finding ESCA molecular biomarkers. Results & conclusion: We identified 103 epigenetic markers (including 54 genome-wide and 49 promoter markers) and 37 genetic markers for ESCA. These markers provide new molecular biomarkers for ESCA diagnosis, prognosis and therapy. Importantly, this study provides a new pipeline for finding new molecular markers for cancers from cfDNA by combining SALP-seq and machine learning. Finally, by finding new molecular markers for ESCA from cfDNA, this study sheds important new insights on the clinical worth of cfDNA. 2 the incidence of cancer has not changed significantly before, cancer mortality has continued to decline, not only because of the development of medical standards, but also for preventive screening.Tissue biopsy is still the gold standard for diagnosing tumors, but due to the traumatic nature of patients, it brings a lot of interference to the dynamic treatment of patients. There are also many risks and ethical issues in tissue biopsy, which makes it have certain limitations. Liquid biopsy is a kind of cutting-edge technology to analyze a range of tumor material in the blood or other body fluids in a minimally invasive or noninvasive manner. The tumor material includes circulating tumor cells (CTCs), cell-free tumor DNA (ctDNA), messenger RNA (mRNA), microRNA (miRNA), and exosomes. Of these tumor biomarkers, ctDNA are most widely recognized in clinical application 4 . Comparing to ctDNA, cell-free DNA (cfDNA) is a broader term which describes DNA that is freely circulating, but is not necessarily of tumor origin. CtDNA refers to the cfDNA from tumor.CfDNA in human body fluids, such as plasma, was discovered in 1948 5 . Most of the plasma cfDNA originated from the hematopoietic system in healthy subjects, but in clinical patients (e.g. pregnancy and cancer), the related cells/tissues would release additional DNA into the plasma 6,7 . The detection of this perturbation would allow us to diagnose the abnormality for people in a noninvasive way. In recent years, methods based on the analysis of plasma cfDNA which is as an emerging technology have been largely explored for noninvasive prenatal testing (NIPT) and cancer liquid biopsy 8,9...

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“…(4) Non-random fragmentation: cfDNA fragments have preferred start and end positions [14], so true mutations could cluster at certain positions on the supporting reads. Conventional tools which assume randomly fragmented genomic DNA tend to classify mutation candidates with clustered positions as misalignment artifacts, eliminating them.…”

Section: Cfsnvmentioning

confidence: 99%

“…WES is increasingly popular, but does not permit deep sequencing. (3) They do not exploit two key features of cfDNA, namely short fragment size (~166 bp on average) and non-random fragmentation [14,15]. Therefore, we have developed a revolutionary cfDNA SNV caller named cfSNV.…”

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confidence: 99%

Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis

Noor

Zeng

et al. 2020

Preprint

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Liquid biopsy using cell-free DNA (cfDNA) is attractive for a wide range of clinical applications, including cancer detection, locating, and monitoring. However, developing these applications requires precise and sensitive calling of somatic single nucleotide variations (SNVs) from cfDNA sequencing data. To date, no SNV caller addresses all the special challenges of cfDNA to provide reliable results. Here we present cfSNV, a revolutionary somatic SNV caller with five innovative techniques to overcome and exploit the unique properties of cfDNA. cfSNV provides hierarchical mutation profiling, thanks to complete coverage of the clonal landscape by cfSNV, and multi-layer error suppression. In both simulated datasets and real patient data, we demonstrate that cfSNV is superior to existing tools, especially for low-frequency somatic SNVs. We also show how the five novel techniques contribute to its performance. Further, we demonstrate a clinical application using cfSNV to select non-small-cell lung cancer patients for immunotherapy treatment.

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Preferred end coordinates and somatic variants as signatures of circulating tumor DNA associated with hepatocellular carcinoma

Cited by 173 publications

References 26 publications

Identification and characterization of extrachromosomal circular DNA in maternal plasma

Identification and characterization of extrachromosomal circular DNA in maternal plasma

Finding new cancer epigenetic and genetic biomarkers from cell-free DNA by combining SALP-seq and machine learning: esophageal cancer as an example

Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis

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