Integrating genomic features for non-invasive early lung cancer detection

被引：481

作者：

Chabon, Jacob J. ^{[1
,2
]}

Hamilton, Emily G. ^{[3
]}

Kurtz, David M. ^{[4
,5
,6
]}

Esfahani, Mohammad S. ^{[1
,4
]}

Moding, Everett J. ^{[1
,7
]}

Stehr, Henning ^{[8
]}

Schroers-Martin, Joseph ^{[4
,5
]}

Nabet, Barzin Y. ^{[1
,7
]}

Chen, Binbin ^{[4
,9
]}

Chaudhuri, Aadel A. ^{[10
,11
,12
]}

Liu, Chih Long ^{[4
]}

Hui, Angela B. ^{[1
,7
]}

Jin, Michael C. ^{[4
]}

Azad, Tej D. ^{[4
]}

Almanza, Diego ^{[3
]}

Jeon, Young-Jun ^{[1
]}

Nesselbush, Monica C. ^{[3
]}

Keh, Lyron Co Ting ^{[1
]}

Bonilla, Rene F. ^{[7
]}

Yoo, Christopher H. ^{[7
]}

Ko, Ryan B. ^{[7
]}

Chen, Emily L. ^{[7
]}

Merriott, David J. ^{[7
]}

Massion, Pierre P. ^{[13
,14
]}

Mansfield, Aaron S. ^{[15
]}

Jen, Jin ^{[16
]}

Ren, Hong Z. ^{[16
]}

Lin, Steven H. ^{[17
]}

Costantino, Christina L. ^{[18
,19
]}

Burr, Risa ^{[18
,20
]}

Tibshirani, Robert ^{[21
,22
]}

Gambhir, Sanjiv S. ^{[6
,23
]}

Berry, Gerald J. ^{[8
]}

Jensen, Kristin C. ^{[8
,24
]}

West, Robert B. ^{[8
]}

Neal, Joel W. ^{[4
]}

Wakelee, Heather A. ^{[4
]}

Loo, Billy W., Jr. ^{[7
]}

Kunder, Christian A. ^{[8
]}

Leung, Ann N. ^{[23
]}

Lui, Natalie S. ^{[25
]}

Berry, Mark F. ^{[25
]}

Shrager, Joseph B. ^{[24
,25
]}

Nair, Viswam S. ^{[23
,26
,27
]}

Haber, Daniel A. ^{[18
,20
,28
]}

Sequist, Lecia V. ^{[18
,28
]}

Alizadeh, Ash A. ^{[1
,2
,4
,5
]}

Diehn, Maximilian ^{[1
,2
,7
]}

机构：

[1] Stanford Univ, Stanford Canc Inst, Stanford, CA 94305 USA

[2] Stanford Univ, Inst Stem Cell Biol & Regenerat Med, Stanford, CA 94305 USA

[3] Stanford Univ, Program Canc Biol, Stanford, CA USA

[4] Stanford Univ, Dept Med, Div Oncol, Stanford, CA 94305 USA

[5] Stanford Univ, Dept Med, Div Hematol, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA

[8] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[10] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO USA

[11] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA

[12] Washington Univ, Sch Med, Siteman Canc Ctr, St Louis, MO USA

[13] Vanderbilt Univ, Med Ctr, Div Allergy Pulm & Crit Care Med, Nashville, TN USA

[14] Tennessee Valley Healthcare Syst, Vet Affairs, Nashville, TN USA

[15] Mayo Clin, Dept Oncol, Div Med Oncol, Rochester, MN USA

[16] Mayo Clin, Div Expt Pathol, Dept Lab Med & Pathol, Rochester, MN USA

[17] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[18] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02115 USA

[19] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02115 USA

[20] Howard Hughes Med Inst, Chevy Chase, MD USA

[21] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[22] Stanford Univ, Dept Biomed Data Sci, Stanford, CA 94305 USA

[23] Stanford Univ, Dept Radiol, Stanford, CA 94305 USA

[24] VA Palo Alto Healthcare Syst, Stanford, CA USA

[25] Stanford Univ, Dept Cardiothorac Surg, Div Thorac Surg, Stanford, CA 94305 USA

[26] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

[27] Univ Washington, Div Pulm Crit Care & Sleep Med, Seattle, WA 98195 USA

[28] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA

来源：

NATURE | 2020年 / 580卷 / 7802期

基金：

美国国家卫生研究院;

关键词：

DNA; PLASMA; NUMBER;

D O I：

10.1038/s41586-020-2140-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening. Radiologic screening of high-risk adults reduces lung-cancer-related mortality(1,2); however, a small minority of eligible individuals undergo such screening in the United States(3,4). The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)(5), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

引用

页码：245 / +

页数：34

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