CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data

Li, Wenyuan; Li, Qingjiao; Kang, Shuli; Same, Mary; Zhou, Yonggang; Sun, Carol K.; Liu, Chun-Chi; Matsuoka, Lea; Sher, Linda; Wong, Wing Hung; Alber, Frank; Zhou, Xianghong Jasmine

doi:10.1093/nar/gky423

Cited by 153 publications

(178 citation statements)

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“…Our work provides a proof of concept for the utility of plasma methylome deconvolution in 359 studying human tissue dynamics in health and disease, adding insights beyond those of recent 360 reports in this emerging field 19,20,21,22 . Furthermore, our approach can easily be adapted to 361 determine the cellular contributors to cfDNA in virtually any setting in which there is a question 362 12 regarding the composition of cfDNA.…”

mentioning

confidence: 91%

“…In recent years, this understanding 17 has led to the emergence of diagnostic tools, which are impacting multiple areas of medicine. 18 Specifically, next generation sequencing of fetal DNA circulating in maternal blood has allowed 19 non-invasive prenatal testing (NIPT) of fetal chromosomal abnormalities 2,3 ; detection of donor-20 derived DNA in the circulation of organ transplant recipients can be used for early identification 21 of graft rejection 4,5 ; and the evaluation of mutated DNA in circulation can be used to detect, 22 genotype and monitor cancer 1,6 . These technologies are powerful at identifying genetic 23 anomalies in circulating DNA, yet are not informative when cfDNA does not carry mutations.…”

Section: Introductionmentioning

confidence: 99%

“…Guo et al demonstrated 48 the potential of cfDNA methylation for detecting cancer as well as identifying its tissue of origin 49 in two cancer types, using a reduced representation bisulfite sequencing (RRBS) approach 20 . 50 Kang et al and Li et al described CancerLocator 21 and CancerDetector 22 , probabilistic 51 approaches for cancer detection based on cfDNA methylation sequencing. 52…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Moss¹,

Magenheim²,

Neiman³

et al. 2018

Preprint

153

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1Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent 2 cell death events in the body. Here, we present an approach for unbiased determination of the 3 tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. 4The method is validated using in silico simulations as well as in vitro mixes of DNA from 5 different tissue sources at known proportions. We show that plasma cfDNA of healthy donors 6 originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial 7 cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue 8 contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the 9 colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure 10 which can be easily adapted to study the cellular contributors to cfDNA in many settings, 11 opening a broad window into healthy and pathologic human tissue dynamics. 12 13

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mentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Moss¹,

Magenheim²,

Neiman³

et al. 2018

Preprint

153

320

View full text Add to dashboard Cite

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“…We have further developed a general DNA methylation-based approach for determining the contributions of multiple tissue types into the cfDNA pool, a method that we have named "plasma DNA tissue mapping" (Sun et al 2015). This principle has also been utilized to predict the tissue origin of tumors by other researchers (Kang et al 2017;Li et al 2018). These published approaches used whole-genome bisulfite sequencing (BS-seq) of plasma DNA (Lister et al 2008;Lun et al 2013;Chan et al 2013a).…”

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confidence: 99%

Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

et al. 2019

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Cell-free DNA (cfDNA) in human plasma is a class of biomarkers with many current and potential future diagnostic applications. Recent studies have shown that cfDNA molecules are not randomly fragmented and possess information related to their tissues of origin. Pathologies causing death of cells from particular tissues result in perturbations in the relative distribution of DNA from the affected tissues. Such tissue-of-origin analysis is particularly useful in the development of liquid biopsies for cancer. It is therefore of value to accurately determine the relative contributions of the tissues to the plasma DNA pool in a simultaneous manner. In this work, we report that in open chromatin regions, cfDNA molecules show characteristic fragmentation patterns reflected by sequencing coverage imbalance and differentially phased fragment end signals. The latter refers to differences in the read densities of sequences corresponding to the orientation of the upstream and downstream ends of cfDNA molecules in relation to the reference genome. Such cfDNA fragmentation patterns preferentially occur in tissue-specific open chromatin regions where the corresponding tissues contributed DNA into the plasma. Quantitative analyses of such signals allow measurement of the relative contributions of various tissues toward the plasma DNA pool. These findings were validated by plasma DNA sequencing data obtained from pregnant women, organ transplantation recipients, and cancer patients. Orientation-aware plasma DNA fragmentation analysis therefore has potential diagnostic applications in noninvasive prenatal testing, organ transplantation monitoring, and cancer liquid biopsy.

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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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CancerDetector: ultrasensitive and non-invasive cancer detection at the resolution of individual reads using cell-free DNA methylation sequencing data

Cited by 153 publications

References 40 publications

Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease

Orientation-aware plasma cell-free DNA fragmentation analysis in open chromatin regions informs tissue of origin

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

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