Enhanced detection of circulating tumor DNA by fragment size analysis

Florent Mouliere , Dineika Chandrananda , Anna M. Piskorz , Elisabeth K. Moore , James Morris , Lise Barlebo Ahlborn , Richard Mair , Teodora Goranova , Francesco Marass , Katrin Heider , Jonathan C. M. Wan , Anna Supernat , Irena Hudecova , Ioannis Gounaris , Susana Ros , Mercedes Jimenez-Linan , Javier Garcia-Corbacho , Keval Patel , Olga Østrup , Suzanne Murphy , Matthew D. Eldridge , Davina Gale , Grant D. Stewart , Johanna Burge , Wendy N. Cooper , Michiel S. van der Heijden , Charles E. Massie , Colin Watts , Pippa Corrie , Simon Pacey , Kevin Brindle , Richard D. Baird , Morten Mau-Sørensen , Christine A. Parkinson , Christopher G. Smith , James D. Brenton , Nitzan Rosenfeld

Abstract

Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
Author Florent Mouliere
Florent Mouliere,,
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, Dineika Chandrananda
Dineika Chandrananda,,
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, Anna M. Piskorz
Anna M. Piskorz,,
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, Elisabeth K. Moore
Elisabeth K. Moore,,
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, James Morris
James Morris,,
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, Lise Barlebo Ahlborn
Lise Barlebo Ahlborn,,
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, Richard Mair
Richard Mair,,
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, Teodora Goranova
Teodora Goranova,,
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, Francesco Marass
Francesco Marass,,
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, Katrin Heider
Katrin Heider,,
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et al.`
Journal seriesScience Translational Medicine, ISSN 1946-6234, (A 50 pkt)
Issue year2018
Vol10
No466
Pages1-28
Publication size in sheets1.35
Article numbereaat4921
ASJC Classification2700 General Medicine
DOIDOI:10.1126/scitranslmed.aat4921
URL https://doi.org/10.1126/scitranslmed.aat4921
Languageen angielski
Score (nominal)50
ScoreMinisterial score = 50.0, 30-05-2019, ArticleFromJournal
Ministerial score (2013-2016) = 50.0, 30-05-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 3.104; WoS Impact Factor: 2017 = 16.71 (2) - 2017=18.614 (5)
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