Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing

Sun, Kun; Jiang, Peiyong; Wong, Ada I. C.; Cheng, Yvonne Kwun Yue; Cheng, Suk Hang; Zhang, Haiqiang; Chan, K. C. Allen; Leung, Tak Yeung; Chiu, Rossa W.̉K.; Lo, Y.M. Dennis

doi:10.1073/pnas.1804134115

Cited by 111 publications

(122 citation statements)

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“…Similarly, in lung cancer, melanoma and colorectal cancer, fragment sizes of cfDNA derived from tumor were short . Recent research reported that higher nucleosome accessibility allowed endonuclease enzymes to cut gDNA within the nucleosome cores, contributing to a preponderance of shorter cfDNA . Further elucidation of the molecular mechanisms behind cfDNA fragmentation is needed.…”

Section: Discussionmentioning

confidence: 99%

“…39,40 Recent research reported that higher nucleosome accessibility allowed endonuclease enzymes to cut gDNA within the nucleosome cores, contributing to a preponderance of shorter cfDNA. 41 Further elucidation of the molecular mechanisms behind cfDNA fragmentation is needed. Second, some mutations could be detected in both cfDNA and gDNA from F I G U R E 6 Positive circulating tumor DNA (ctDNA) and short fragment size of plasma cell-free DNA (cfDNA) were associated with poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

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Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

et al. 2019

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Reliable biomarkers for renal cell carcinoma (RCC) have yet to be determined. Circulating tumor DNA (ctDNA) is an emerging resource to detect and monitor molecular characteristics of various tumors. The present study aims to clarify the clinical utility of ctDNA for RCC. Fifty‐three patients histologically diagnosed with clear cell RCC were enrolled. Targeted sequencing was carried out using plasma cell‐free DNA (cfDNA) and tumor DNA. We applied droplet digital PCR (ddPCR) to validate detected mutations. cfDNA fragment size was also evaluated using a microfluidics‐based platform and sequencing. Proportion of cfDNA fragments was defined as the ratio of small (50‐166 bp) to large (167‐250 bp) cfDNA fragments. Association of mutant allele frequency of ctDNA with clinical course was analyzed. Prognostic potential was evaluated using log‐rank test. A total of 38 mutations across 16 (30%) patients were identified from cfDNA, including mutations in TP53 (n = 6) and VHL (n = 5), and median mutant allele frequency of ctDNA was 10%. We designed specific ddPCR probes for 11 mutations and detected the same mutations in both cfDNA and tumor DNA. Positive ctDNA was significantly associated with a higher proportion of cfDNA fragments (P = .033), indicating RCC patients with ctDNA had shorter fragment sizes of cfDNA. Interestingly, the changes of mutant allele frequency in ctDNA concurrently correlated with clinical course. Positive ctDNA and fragmentation of cfDNA were significantly associated with poor cancer‐specific survival (P < .001, P = .011). In conclusion, our study shows the clinical utility of ctDNA status and cfDNA fragment size as biomarkers for prognosis and disease monitoring in RCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

et al. 2019

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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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“…The emerging knowledge base on the fundamental biology of cfDNA has been called “fragmentomics.” Compared to maternal cfDNA, cfDNA of fetal origin is shorter, differentially methylated, contains a “nucleosome footprint” that reflects a nonrandom fragmentation pattern, and has characteristic end sites that differ from maternal fragments …”

Section: Fragmentomicsmentioning

confidence: 99%

“…Compared to maternal cfDNA, cfDNA of fetal origin is shorter, 8,9 differentially methylated, 10,11 contains a "nucleosome footprint" that reflects a nonrandom fragmentation pattern, 12 and has characteristic end sites that differ from maternal fragments. 13 In 2019, pioneering researchers at the Li Ka Shing Institute of Health Sciences consolidated these understandings of fetal cfDNA in a publication that opens further opportunities for prenatal diagnosis, oncology, and transplant medicine. In this proof-of-principle study, the authors proposed a new method for nucleosome positioning profiling and quantitative determination of the relative contributions of various tissues in plasma DNA by fragmentation pattern analyses.…”

Section: Fragmentomicsmentioning

confidence: 99%

In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2019

et al. 2020

View full text Add to dashboard Cite

Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing

Cited by 111 publications

References 54 publications

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma

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

In case you missed it: The Prenatal Diagnosis editors bring you the most significant advances of 2019

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