Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing

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Abstract

The Oxford Nanopore (ONT) platform provides portable and rapid genome sequencing, and its ability to natively profile DNA methylation without complex sample processing is attractive for point-of-care real-time sequencing. We recently demonstrated ONT shallow whole-genome sequencing to detect copy number alterations (CNAs) from the circulating tumor DNA (ctDNA) of cancer patients. Here, we show that cell type and cancer-specific methylation changes can also be detected, as well as cancer-associated fragmentation signatures. This feasibility study suggests that ONT shallow WGS could be a powerful tool for liquid biopsy.

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Supplementary Information

The online version contains supplementary material available at 10.1186/s13059-022-02710-1.

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Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study

Hana Storkanova, Sabina Oreska, Maja Spiritovic … (2021)

Our previous study demonstrated increased expression of Heat shock protein (Hsp) 90 in the skin of patients with systemic sclerosis (SSc). We aimed to evaluate plasma Hsp90 in SSc and characterize its association with SSc-related features. Ninety-two SSc patients and 92 age-/sex-matched healthy controls were recruited for the cross-sectional analysis. The longitudinal analysis comprised 30 patients with SSc associated interstitial lung disease (ILD) routinely treated with cyclophosphamide. Hsp90 was increased in SSc compared to healthy controls. Hsp90 correlated positively with C-reactive protein and negatively with pulmonary function tests: forced vital capacity and diffusing capacity for carbon monoxide (DLCO). In patients with diffuse cutaneous (dc) SSc, Hsp90 positively correlated with the modified Rodnan skin score. In SSc-ILD patients treated with cyclophosphamide, no differences in Hsp90 were found between baseline and after 1, 6, or 12 months of therapy. However, baseline Hsp90 predicts the 12-month change in DLCO. This study shows that Hsp90 plasma levels are increased in SSc patients compared to age-/sex-matched healthy controls. Elevated Hsp90 in SSc is associated with increased inflammatory activity, worse lung functions, and in dcSSc, with the extent of skin involvement. Baseline plasma Hsp90 predicts the 12-month change in DLCO in SSc-ILD patients treated with cyclophosphamide.

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Genome-wide cell-free DNA fragmentation in patients with cancer

Stephen Cristiano, Alessandro I. Cavalcanti Leal, Jillian Phallen … (2019)

Cell-free DNA (cfDNA) in the blood provides a noninvasive diagnostic avenue for patients with cancer 1 . However, characteristics of the origins and molecular features of cfDNA are poorly understood. We developed an approach to evaluate fragmentation patterns of cfDNA across the genome and found that cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation profiles. We applied this method to analyze fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer and 245 healthy individuals. A machine learning model incorporating genome-wide fragmentation features had sensitivities of detection ranging from 57% to >99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation based cfDNA analyses detected 91% of cancer patients. The results of these analyses highlight important properties of cfDNA and provide a proof of principle approach for screening, early detection, and monitoring of human cancer.

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SAMBLASTER: fast duplicate marking and structural variant read extraction

Gregory Faust, Ira Hall (2014)

Motivation: Illumina DNA sequencing is now the predominant source of raw genomic data, and data volumes are growing rapidly. Bioinformatic analysis pipelines are having trouble keeping pace. A common bottleneck in such pipelines is the requirement to read, write, sort and compress large BAM files multiple times. Results: We present SAMBLASTER, a tool that reduces the number of times such costly operations are performed. SAMBLASTER is designed to mark duplicates in read-sorted SAM files as a piped post-pass on DNA aligner output before it is compressed to BAM. In addition, it can simultaneously output into separate files the discordant read-pairs and/or split-read mappings used for structural variant calling. As an alignment post-pass, its own runtime overhead is negligible, while dramatically reducing overall pipeline complexity and runtime. As a stand-alone duplicate marking tool, it performs significantly better than PICARD or SAMBAMBA in terms of both speed and memory usage, while achieving nearly identical results. Availability and implementation: SAMBLASTER is open-source C++ code and freely available for download from https://github.com/GregoryFaust/samblaster. Contact: imh4y@virginia.edu

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Author and article information

Contributors

Silvestro G. Conticello:

ORCID: http://orcid.org/0000-0002-4244-1846

silvestro.conticello@cnr.it

Benjamin P. Berman:

ORCID: http://orcid.org/0000-0002-2099-9005

ben.berman@mail.huji.ac.il

Journal

Journal ID (nlm-ta): Genome Biol

Journal ID (iso-abbrev): Genome Biol

Title: Genome Biology

Publisher: BioMed Central (London )

ISSN (Print): 1474-7596

ISSN (Electronic): 1474-760X

Publication date (Electronic): 15 July 2022

Publication date PMC-release: 15 July 2022

Publication date Collection: 2022

Volume: 23

Electronic Location Identifier: 158

Affiliations

[1 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Faculty of Medicine, , The Hebrew University of Jerusalem, ; Jerusalem, Israel

[2 ]GRID grid.417623.5, ISNI 0000 0004 1758 0566, Core Research Laboratory, ISPRO, ; Florence, Italy

[3 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Department of Oncology, Hadassah Medical Center, Faculty of Medicine, , Hebrew University of Jerusalem, ; Jerusalem, Israel

[4 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Department of Cell and Developmental Biology, The Alexander Silberman Institute of Life Sciences, , The Hebrew University of Jerusalem, ; Jerusalem, Israel

[5 ]GRID grid.144189.1, ISNI 0000 0004 1756 8209, Unit of Respiratory Medicine, Department of Critical Area and Surgical, Medical and Molecular Pathology, , University Hospital of Pisa, ; Pisa, Italy

[6 ]GRID grid.418529.3, ISNI 0000 0004 1756 390X, Institute of Clinical Physiology, National Research Council, ; Pisa, Italy

Author information

Efrat Katsman http://orcid.org/0000-0002-4897-8783

Shari Orlanski http://orcid.org/0000-0003-4739-6113

Filippo Martignano http://orcid.org/0000-0001-7564-9224

Ilana Fox-Fisher http://orcid.org/0000-0002-3773-9330

Ruth Shemer http://orcid.org/0000-0003-0625-475X

Yuval Dor http://orcid.org/0000-0003-2456-2289

Aviad Zick http://orcid.org/0000-0002-5077-9249

Amir Eden http://orcid.org/0000-0002-9121-6258

Iacopo Petrini http://orcid.org/0000-0002-7752-6866

Silvestro G. Conticello http://orcid.org/0000-0002-4244-1846

Benjamin P. Berman http://orcid.org/0000-0002-2099-9005

Article

Publisher ID: 2710

DOI: 10.1186/s13059-022-02710-1

PMC ID: 9283844

PubMed ID: 35841107

SO-VID: a1b99988-d56d-49ac-9d2a-eb2685d21907

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 11 October 2021

Date accepted : 15 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003196, Ministero della Salute;

Award ID: SG-2019-12370279

Award Recipient : Filippo Martignano

Funded by: FundRef http://dx.doi.org/10.13039/100001698, Israel Cancer Research Fund;

Award ID: 845755

Award Recipient : Benjamin P. Berman

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ScienceOpen disciplines: Genetics

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Detecting cell-of-origin and cancer-specific methylation features of cell-free DNA from Nanopore sequencing

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Abstract

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Supplementary Information

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Evolutionary Cell Biology

Most cited references 34

Plasma Hsp90 levels in patients with systemic sclerosis and relation to lung and skin involvement: a cross-sectional and longitudinal study

Genome-wide cell-free DNA fragmentation in patients with cancer

SAMBLASTER: fast duplicate marking and structural variant read extraction

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Cited by 22

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