TY - JOUR
T1 - Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA
AU - Kurtz, David M.
AU - Soo, Joanne
AU - Co Ting Keh, Lyron
AU - Alig, Stefan
AU - Chabon, Jacob J.
AU - Sworder, Brian J.
AU - Schultz, Andre
AU - Jin, Michael C.
AU - Scherer, Florian
AU - Garofalo, Andrea
AU - Macaulay, Charles W.
AU - Hamilton, Emily G.
AU - Chen, Binbin
AU - Olsen, Mari
AU - Schroers-Martin, Joseph G.
AU - Craig, Alexander F.M.
AU - Moding, Everett J.
AU - Esfahani, Mohammad S.
AU - Liu, Chih Long
AU - Dührsen, Ulrich
AU - Hüttmann, Andreas
AU - Casasnovas, René Olivier
AU - Westin, Jason R.
AU - Roschewski, Mark
AU - Wilson, Wyndham H.
AU - Gaidano, Gianluca
AU - Rossi, Davide
AU - Diehn, Maximilian
AU - Alizadeh, Ash A.
N1 - Funding Information:
D.M.K. reports paid consultancy from Roche and Genentech. A.A.A. reports research funding from Celgene and Pfizer, ownership interests in FortySeven and CiberMed, and paid consultancy from Roche, Genentech, Janssen, Pharmacyclics, Gilead, Celgene and Chugai. M.D. reports research funding from Varian Medical Systems, AstraZeneca and Illumina, ownership interest in CiberMed, and paid consultancy from Roche, AstraZeneca, Novartis, Genentech, Illumina, RefleXion, Gritstone Oncology, Boehringer Ingelheim and BioNTech. M.D., A.A.A., D.M.K., J.C. and M.S.E. report patent filings related to cancer biomarkers. M.D., A.A.A., D.M.K. and J.C. report ownership interest in Foresight Diagnostics. R.O.C. is a member of the Roche advisory board and received research support from Roche. D.R. received research support from Gilead, Janssen, Roche and AbbVie, outside the submitted work. E.J.M. has served as a paid consultant for DeciBio. The remaining authors declare no competing interests.
Funding Information:
This work was supported by the National Cancer Institute (R01CA233975 and R01CA188298 to A.A.A. and M.D.; K08CA241076 to D.M.K.), the Virginia and D. K. Ludwig Fund for Cancer Research (A.A.A. and M.D.), the Bakewell Foundation (A.A.A. and M.D.), the Damon Runyon Cancer Research Foundation (PST no. 09-16 to D.M.K. and DR-CI no. 71-14 to A.A.A.), the American Society of Hematology Scholar Award (A.A.A.), the V Foundation for Cancer Research Abeloff Scholar Award (A.A.A.), the Conquer Cancer Foundation of the American Society of Clinical Oncology (D.M.K.), the Emerson Collective Cancer Research Fund (A.A.A.), the Stinehart/Reed Award (A.A.A.), the CRK Faculty Scholar Fund (M.D.) and the SDW/DT and Shanahan Family Foundations (A.A.A.). A.A.A. is a Scholar of The Leukemia & Lymphoma Society.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85111152480&partnerID=8YFLogxK
U2 - 10.1038/s41587-021-00981-w
DO - 10.1038/s41587-021-00981-w
M3 - Article
C2 - 34294911
AN - SCOPUS:85111152480
SN - 1087-0156
VL - 39
SP - 1537
EP - 1547
JO - Nature biotechnology
JF - Nature biotechnology
IS - 12
ER -