Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA

被引：233

作者：

Kurtz, David M. ^{[1
]}

Soo, Joanne ^{[1
,2
]}

Keh, Lyron Co Ting ^{[1
]}

Alig, Stefan ^{[1
]}

Chabon, Jacob J. ^{[2
,3
,16
]}

Sworder, Brian J. ^{[1
]}

Schultz, Andre ^{[2
]}

Jin, Michael C. ^{[1
]}

Scherer, Florian ^{[1
,17
]}

Garofalo, Andrea ^{[1
]}

Macaulay, Charles W. ^{[1
]}

Hamilton, Emily G. ^{[4
]}

Chen, Binbin ^{[5
]}

Olsen, Mari ^{[1
]}

Schroers-Martin, Joseph G. ^{[6
]}

Craig, Alexander F. M. ^{[1
]}

Moding, Everett J. ^{[7
]}

Esfahani, Mohammad S. ^{[1
]}

Liu, Chih Long ^{[1
]}

Duehrsen, Ulrich ^{[8
]}

Huettmann, Andreas ^{[8
]}

Casasnovas, Rene-Olivier ^{[9
,10
]}

Westin, Jason R. ^{[11
]}

Roschewski, Mark ^{[12
]}

Wilson, Wyndham H. ^{[12
]}

Gaidano, Gianluca ^{[13
]}

Rossi, Davide ^{[14
,15
]}

Diehn, Maximilian ^{[2
,3
,7
]}

Alizadeh, Ash A. ^{[1
,2
,3
,6
]}

机构：

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

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

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

[4] Stanford Univ, Program Canc Biol, Stanford, CA 94305 USA

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

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

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

[8] Univ Hosp Essen, West German Canc Ctr Essen, Dept Hematol & Stem Cell Transplantat, Essen, Germany

[9] CHU Dijon, Hop F Mitterrand, Dept Hematol, Dijon, France

[10] INSERM, Dijon, France

[11] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma Myeloma, Houston, TX 77030 USA

[12] NCI, Lymphoid Malignancies Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[13] Univ Piemonte Orientale, Dept Translat Med, Div Hematol, Novara, Italy

[14] Oncol Inst Southern Switzerland, Hematol, Bellinzona, Switzerland

[15] Oncol Res Inst, Bellinzona, Switzerland

[16] Foresight Diagnost, Aurora, CO USA

[17] Univ Freiburg, Fac Med, Med Ctr, Dept Med, Freiburg, Germany

来源：

NATURE BIOTECHNOLOGY | 2021年 / 39卷 / 12期

关键词：

B-CELL LYMPHOMA; MUTATIONAL PROCESSES; CANCER; GENOME; GENE; AID; HYPERMUTATION; PATHOGENESIS; SIGNATURES; PLASMA;

D O I：

10.1038/s41587-021-00981-w

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.

引用

页码：1537 / +

页数：24

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