Enhanced detection of circulating tumor DNA by fragment size analysis.
Enhanced detection of circulating tumor DNA by fragment size analysis.
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通过碎片尺寸分析增强了循环肿瘤DNA的检测。
DOI：
10.1126/scitranslmed.aat4921
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发表时间：
2018-11-07
影响因子：
17.1
通讯作者：
Rosenfeld N
中科院分区：
文献类型：
--
作者：
Mouliere F;Chandrananda D;Piskorz AM;Moore EK;Morris J;Ahlborn LB;Mair R;Goranova T;Marass F;Heider K;Wan JCM;Supernat A;Hudecova I;Gounaris I;Ros S;Jimenez-Linan M;Garcia-Corbacho J;Patel K;Østrup O;Murphy S;Eldridge MD;Gale D;Stewart GD;Burge J;Cooper WN;van der Heijden MS;Massie CE;Watts C;Corrie P;Pacey S;Brindle KM;Baird RD;Mau-Sørensen M;Parkinson CA;Smith CG;Brenton JD;Rosenfeld N
现有的改善循环肿瘤DNA（ctDNA）检测的方法主要集中在检测基因组变异的灵敏度上，但很少考虑血浆无细胞DNA（cfDNA）的生物学特性。我们假设循环DNA片段长度的差异可以用来提高检测ctDNA存在和癌症非侵入性基因组分析的灵敏度。我们使用低通全基因组测序（0.4×）调查了来自200名癌症患者的344份血浆样本中的ctDNA片段大小。为了确定突变ctDNA的大小分布，在19名患者中进行了肿瘤引导的个性化深度测序。我们检测到90-150 bp片段大小的ctDNA富集，并开发了这些片段的体外和计算机大小选择方法。选择90-150 bp之间的片段改善了肿瘤DNA的检测，在>95%的病例中具有超过2倍的中值富集，并且在>10%的病例中具有超过4倍的富集。大小选择的cfDNA的分析鉴定了在其他情况下未检测到的临床上可行的突变和拷贝数改变。通过整合cfDNA的片段长度和拷贝数分析的预测模型改进了对来自晚期癌症患者的血浆样品的鉴定，与没有片段化特征的AUC<0.80相比，AUC>0.99。与没有片段化特征的AUC<0.5相比，在AUC>0.91的情况下，实现了对来自患有神经胶质瘤、肾癌和胰腺癌的患者的cfDNA的鉴定增加。片段大小分析和特定片段大小的选择性测序可以促进ctDNA检测，并且可以补充或提供游离DNA的更深测序的替代方案，用于临床应用、早期诊断和肿瘤生物学研究。
Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on sensitivity for detecting 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 non-invasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 cancer patients 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 90–150 bp, and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90–150 bp improved detection of tumor DNA, with more than 2-fold median enrichment in >95% of cases, and more than 4-fold 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 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 cell-free DNA for clinical applications, earlier diagnosis and study of tumor biology.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
DOI：
10.1073/pnas.1500076112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Jiang, Peiyong;Chan, Carol W. M.;Lo, Y. M. Dennis
通讯作者：
Lo, Y. M. Dennis
DOI：
10.1073/pnas.0507904102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Diehl, F;Li, M;Vogelstein, B
通讯作者：
Vogelstein, B
影响因子：
64.8
作者：
Abbosh C;Birkbak NJ;Wilson GA;Jamal-Hanjani M;Constantin T;Salari R;Le Quesne J;Moore DA;Veeriah S;Rosenthal R;Marafioti T;Kirkizlar E;Watkins TBK;McGranahan N;Ward S;Martinson L;Riley J;Fraioli F;Al Bakir M;Grönroos E;Zambrana F;Endozo R;Bi WL;Fennessy FM;Sponer N;Johnson D;Laycock J;Shafi S;Czyzewska-Khan J;Rowan A;Chambers T;Matthews N;Turajlic S;Hiley C;Lee SM;Forster MD;Ahmad T;Falzon M;Borg E;Lawrence D;Hayward M;Kolvekar S;Panagiotopoulos N;Janes SM;Thakrar R;Ahmed A;Blackhall F;Summers Y;Hafez D;Naik A;Ganguly A;Kareht S;Shah R;Joseph L;Marie Quinn A;Crosbie PA;Naidu B;Middleton G;Langman G;Trotter S;Nicolson M;Remmen H;Kerr K;Chetty M;Gomersall L;Fennell DA;Nakas A;Rathinam S;Anand G;Khan S;Russell P;Ezhil V;Ismail B;Irvin-Sellers M;Prakash V;Lester JF;Kornaszewska M;Attanoos R;Adams H;Davies H;Oukrif D;Akarca AU;Hartley JA;Lowe HL;Lock S;Iles N;Bell H;Ngai Y;Elgar G;Szallasi Z;Schwarz RF;Herrero J;Stewart A;Quezada SA;Peggs KS;Van Loo P;Dive C;Lin CJ;Rabinowitz M;Aerts HJWL;Hackshaw A;Shaw JA;Zimmermann BG;TRACERx consortium;PEACE consortium;Swanton C
通讯作者：
Swanton C
影响因子：
2.7
作者：
Chandrananda D;Thorne NP;Bahlo M
通讯作者：
Bahlo M