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

ABSTRACT: Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value 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 cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.

SUBMITTER: Cristiano S

PROVIDER: S-EPMC6774252 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Cristiano Stephen S Leal Alessandro A Phallen Jillian J Fiksel Jacob J Adleff Vilmos V Bruhm Daniel C DC Jensen Sarah Østrup SØ Medina Jamie E JE Hruban Carolyn C White James R JR Palsgrove Doreen N DN Niknafs Noushin N Anagnostou Valsamo V Forde Patrick P Naidoo Jarushka J Marrone Kristen K Brahmer Julie J Woodward Brian D BD Husain Hatim H van Rooijen Karlijn L KL Ørntoft Mai-Britt Worm MW Madsen Anders Husted AH van de Velde Cornelis J H CJH Verheij Marcel M Cats Annemieke A Punt Cornelis J A CJA Vink Geraldine R GR van Grieken Nicole C T NCT Koopman Miriam M Fijneman Remond J A RJA Johansen Julia S JS Nielsen Hans Jørgen HJ Meijer Gerrit A GA Andersen Claus Lindbjerg CL Scharpf Robert B RB Velculescu Victor E VE

Nature 20190529 7761

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer<sup>1</sup>. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to a ...[more]

PMID: 31142840

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Project description:Unique bits of genetic, biological and pathological information occur in differently sized cell-free DNA (cfDNA) populations. This is a significant discovery, but much of the phenomenon remains to be explored. We investigated cfDNA fragmentation patterns in cultured human bone cancer (143B) cells using increasingly sensitive electrophoresis assays, including four automated microfluidic capillary electrophoresis assays from Agilent, i.e., DNA 1000, High Sensitivity DNA, dsDNA 915 and dsDNA 930, and an optimized manual agarose gel electrophoresis protocol. This comparison showed that (i) as the sensitivity and resolution of the sizing methods increase incrementally, additional nucleosomal multiples are revealed (hepta-nucleosomes were detectable with manual agarose gel electrophoresis), while the estimated size range of high molecular weight (HMW) cfDNA fragments narrow correspondingly; (ii) the cfDNA laddering pattern extends well beyond the 1–3 nucleosomal multiples detected by commonly used methods; and (iii) the modal size of HMW cfDNA populations is exaggerated due to the limited resolving power of electrophoresis, and instead consists of several poly-nucleosomal subpopulations that continue the series of DNA laddering. Furthermore, the most sensitive automated assay used in this study (Agilent dsDNA 930) revealed an exponential decay in the relative contribution of increasingly longer cfDNA populations. This power-law distribution suggests the involvement of a stochastic inter-nucleosomal DNA cleavage process, wherein shorter populations accumulate rapidly as they are fed by the degradation of all larger populations. This may explain why similar size profiles have historically been reported for cfDNA populations originating from different processes, such as apoptosis, necrosis, accidental cell lysis and purported active release. These results not only demonstrate the diversity of size profiles generated by different methods, but also highlight the importance of caution when drawing conclusions on the mechanisms that generate different cfDNA size populations, especially when only a single method is used for sizing.

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

Publications

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

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