Enhanced detection of circulating tumor DNA by fragment size analysis

被引：712

作者：

Mouliere, Florent ^{[1
,2
,22
]}

Chandrananda, Dineika ^{[1
,2
]}

Piskorz, Anna M. ^{[1
,2
]}

Moore, Elizabeth K. ^{[1
,2
,3
]}

Morris, James ^{[1
,2
]}

Ahlborn, Lise Barlebo ^{[4
,5
]}

Mair, Richard ^{[1
,2
,6
]}

Goranova, Teodora ^{[1
,2
]}

Marass, Francesco ^{[1
,2
,7
,8
]}

Heider, Katrin ^{[1
,2
]}

Wan, Jonathan C. M. ^{[1
,2
]}

Supernat, Anna ^{[1
,2
,9
,10
]}

Hudecova, Irena ^{[1
,2
]}

Gounaris, Ioannis ^{[1
,2
,3
]}

Ros, Susana ^{[1
,2
]}

Jimenez-Linan, Mercedes ^{[2
,3
]}

Garcia-Corbacho, Javier ^{[11
]}

Patel, Keval ^{[1
,2
]}

Ostrup, Olga ^{[5
]}

Murphy, Suzanne ^{[1
,2
]}

Eldridge, Matthew D. ^{[1
,2
]}

Gale, Davina ^{[1
,2
]}

Stewart, Grant D. ^{[2
,3
,12
]}

Burge, Johanna ^{[2
,12
]}

Cooper, Wendy N. ^{[1
,2
]}

van der Heijden, Michiel S. ^{[13
,14
]}

Massie, Charles E. ^{[1
,2
,15
]}

Watts, Colin ^{[16
]}

Corrie, Pippa ^{[3
]}

Pacey, Simon ^{[3
,15
]}

Brindle, Kevin M. ^{[1
,2
,17
]}

Baird, Richard D. ^{[18
,19
]}

Mau-Sorensen, Morten ^{[4
]}

Parkinson, Christine A. ^{[1
,2
,3
,20
,21
]}

Smith, Christopher G. ^{[1
,2
]}

Brenton, James D. ^{[1
,2
,3
,20
,21
]}

Rosenfeld, Nitzan ^{[1
,2
]}

机构：

[1] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[2] Canc Res UK Cambridge Inst, Canc Res UK Major Ctr Cambridge, Cambridge CB2 0RE, England

[3] Cambridge Univ Hosp NHS Fdn Trust, Cambridge CB2 0QQ, England

[4] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, DK-2100 Copenhagen, Denmark

[5] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark

[6] Univ Cambridge, Dept Clin Neurosci, Div Neurosurg, Cambridge CB2 0QQ, England

[7] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, CH-4058 Basel, Switzerland

[8] Swiss Inst Bioinformat, CH-4058 Basel, Switzerland

[9] Univ Gdansk, Intercollegiate Fac Biotechnol, Dept Med Biotechnol, PL-80211 Gdansk, Poland

[10] Med Univ Gdansk, PL-80211 Gdansk, Poland

[11] Hosp Clin Barcelona, Clin Inst Haematol & Oncol Dis, Clin Trials Unit, Barcelona 17008036, Spain

[12] Univ Cambridge, Dept Surg, Acad Urol Grp, Cambridge CB2 0QQ, England

[13] Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[14] Netherlands Canc Inst, Dept Med Oncol, NL-1066 CX Amsterdam, Netherlands

[15] Univ Cambridge, Dept Oncol, Cambridge CB2 0XZ, England

[16] Univ Birmingham, Inst Canc Genom Sci, Birmingham B15 2TT, W Midlands, England

[17] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England

[18] Canc Res UK Cambridge Ctr, Early Phase Clin Trials Team, Cambridge CB2 0QQ, England

[19] Canc Res UK Cambridge Ctr, Breast Canc Res Team, Cambridge CB2 0QQ, England

[20] Univ Cambridge, Hutchison MRC Res Ctr, Dept Oncol, Cambridge CB2 0XZ, England

[21] NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England

[22] Vrije Univ Amsterdam, Canc Ctr Amsterdam, Dept Pathol, Amsterdam UMC, Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2018年 / 10卷 / 466期

基金：

欧洲研究理事会; 英国工程与自然科学研究理事会; 英国医学研究理事会;

关键词：

CELL-FREE DNA; LUNG-CANCER; PLASMA DNA; LIQUID BIOPSIES; BLOOD-PLASMA; IDENTIFICATION; ORIGIN;

D O I：

10.1126/scitranslmed.aat4921

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 (0.4x). 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.

引用

页数：13

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