Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Viktor A. Adalsteinsson; Gavin Ha; Samuel S. Freeman; Atish D. Choudhury; Daniel G. Stover; Heather A. Parsons; Gregory Gydush; Sarah C. Reed; Denisse Rotem; Justin Rhoades; Denis Loginov; Dimitri Livitz; Daniel Rosebrock; Ignaty Leshchiner; Jaegil Kim; Chip Stewart; Mara Rosenberg; Joshua M. Francis; Cheng Zhong Zhang; Ofir Cohen; Coyin Oh; Huiming Ding; Paz Polak; Max Lloyd; Sairah Mahmud; Karla Helvie; Margaret S. Merrill; Rebecca A. Santiago; Edward P. O'Connor; Seong H. Jeong; Rachel Leeson; Rachel M. Barry; Joseph F. Kramkowski; Zhenwei Zhang; Laura Polacek; Jens G. Lohr; Molly Schleicher; Emily Lipscomb; Andrea Saltzman; Nelly M. Oliver; Lori Marini; Adrienne G. Waks; Lauren C. Harshman; Sara M. Tolaney; Eliezer M. Van Allen; Eric P. Winer; Nancy U. Lin; Mari Nakabayashi; Mary Ellen Taplin; Cory M. Johannessen; Levi A. Garraway; Todd R. Golub; Jesse S. Boehm; Nikhil Wagle; Gad Getz; J. Christopher Love; Matthew Meyerson

doi:10.1038/s41467-017-00965-y

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Viktor A. Adalsteinsson, Gavin Ha, Samuel S. Freeman, Atish D. Choudhury, Daniel G. Stover, Heather A. Parsons, Gregory Gydush, Sarah C. Reed, Denisse Rotem, Justin Rhoades, Denis Loginov, Dimitri Livitz, Daniel Rosebrock, Ignaty Leshchiner, Jaegil Kim, Chip Stewart, Mara Rosenberg, Joshua M. Francis, Cheng Zhong Zhang, Ofir CohenCoyin Oh, Huiming Ding, Paz Polak, Max Lloyd, Sairah Mahmud, Karla Helvie, Margaret S. Merrill, Rebecca A. Santiago, Edward P. O'Connor, Seong H. Jeong, Rachel Leeson, Rachel M. Barry, Joseph F. Kramkowski, Zhenwei Zhang, Laura Polacek, Jens G. Lohr, Molly Schleicher, Emily Lipscomb, Andrea Saltzman, Nelly M. Oliver, Lori Marini, Adrienne G. Waks, Lauren C. Harshman, Sara M. Tolaney, Eliezer M. Van Allen, Eric P. Winer, Nancy U. Lin, Mari Nakabayashi, Mary Ellen Taplin, Cory M. Johannessen, Levi A. Garraway, Todd R. Golub, Jesse S. Boehm, Nikhil Wagle, Gad Getz, J. Christopher Love, Matthew Meyerson

Research output: Contribution to journal › Article › peer-review

536 Scopus citations

Abstract

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

Original language	English
Article number	1324
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00965-y
State	Published - 1 Dec 2017
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-017-00965-y

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Adalsteinsson, V. A., Ha, G., Freeman, S. S., Choudhury, A. D., Stover, D. G., Parsons, H. A., Gydush, G., Reed, S. C., Rotem, D., Rhoades, J., Loginov, D., Livitz, D., Rosebrock, D., Leshchiner, I., Kim, J., Stewart, C., Rosenberg, M., Francis, J. M., Zhang, C. Z., ... Meyerson, M. (2017). Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nature Communications, 8(1), Article 1324. https://doi.org/10.1038/s41467-017-00965-y

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title = "Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors",

abstract = "Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.",

author = "Adalsteinsson, {Viktor A.} and Gavin Ha and Freeman, {Samuel S.} and Choudhury, {Atish D.} and Stover, {Daniel G.} and Parsons, {Heather A.} and Gregory Gydush and Reed, {Sarah C.} and Denisse Rotem and Justin Rhoades and Denis Loginov and Dimitri Livitz and Daniel Rosebrock and Ignaty Leshchiner and Jaegil Kim and Chip Stewart and Mara Rosenberg and Francis, {Joshua M.} and Zhang, {Cheng Zhong} and Ofir Cohen and Coyin Oh and Huiming Ding and Paz Polak and Max Lloyd and Sairah Mahmud and Karla Helvie and Merrill, {Margaret S.} and Santiago, {Rebecca A.} and O'Connor, {Edward P.} and Jeong, {Seong H.} and Rachel Leeson and Barry, {Rachel M.} and Kramkowski, {Joseph F.} and Zhenwei Zhang and Laura Polacek and Lohr, {Jens G.} and Molly Schleicher and Emily Lipscomb and Andrea Saltzman and Oliver, {Nelly M.} and Lori Marini and Waks, {Adrienne G.} and Harshman, {Lauren C.} and Tolaney, {Sara M.} and {Van Allen}, {Eliezer M.} and Winer, {Eric P.} and Lin, {Nancy U.} and Mari Nakabayashi and Taplin, {Mary Ellen} and Johannessen, {Cory M.} and Garraway, {Levi A.} and Golub, {Todd R.} and Boehm, {Jesse S.} and Nikhil Wagle and Gad Getz and Love, {J. Christopher} and Matthew Meyerson",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00965-y",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Adalsteinsson, VA, Ha, G, Freeman, SS, Choudhury, AD, Stover, DG, Parsons, HA, Gydush, G, Reed, SC, Rotem, D, Rhoades, J, Loginov, D, Livitz, D, Rosebrock, D, Leshchiner, I, Kim, J, Stewart, C, Rosenberg, M, Francis, JM, Zhang, CZ, Cohen, O, Oh, C, Ding, H, Polak, P, Lloyd, M, Mahmud, S, Helvie, K, Merrill, MS, Santiago, RA, O'Connor, EP, Jeong, SH, Leeson, R, Barry, RM, Kramkowski, JF, Zhang, Z, Polacek, L, Lohr, JG, Schleicher, M, Lipscomb, E, Saltzman, A, Oliver, NM, Marini, L, Waks, AG, Harshman, LC, Tolaney, SM, Van Allen, EM, Winer, EP, Lin, NU, Nakabayashi, M, Taplin, ME, Johannessen, CM, Garraway, LA, Golub, TR, Boehm, JS, Wagle, N, Getz, G, Love, JC & Meyerson, M 2017, 'Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors', Nature Communications, vol. 8, no. 1, 1324. https://doi.org/10.1038/s41467-017-00965-y

TY - JOUR

T1 - Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

AU - Adalsteinsson, Viktor A.

AU - Ha, Gavin

AU - Freeman, Samuel S.

AU - Choudhury, Atish D.

AU - Stover, Daniel G.

AU - Parsons, Heather A.

AU - Gydush, Gregory

AU - Reed, Sarah C.

AU - Rotem, Denisse

AU - Rhoades, Justin

AU - Loginov, Denis

AU - Livitz, Dimitri

AU - Rosebrock, Daniel

AU - Leshchiner, Ignaty

AU - Kim, Jaegil

AU - Stewart, Chip

AU - Rosenberg, Mara

AU - Francis, Joshua M.

AU - Zhang, Cheng Zhong

AU - Cohen, Ofir

AU - Oh, Coyin

AU - Ding, Huiming

AU - Polak, Paz

AU - Lloyd, Max

AU - Mahmud, Sairah

AU - Helvie, Karla

AU - Merrill, Margaret S.

AU - Santiago, Rebecca A.

AU - O'Connor, Edward P.

AU - Jeong, Seong H.

AU - Leeson, Rachel

AU - Barry, Rachel M.

AU - Kramkowski, Joseph F.

AU - Zhang, Zhenwei

AU - Polacek, Laura

AU - Lohr, Jens G.

AU - Schleicher, Molly

AU - Lipscomb, Emily

AU - Saltzman, Andrea

AU - Oliver, Nelly M.

AU - Marini, Lori

AU - Waks, Adrienne G.

AU - Harshman, Lauren C.

AU - Tolaney, Sara M.

AU - Van Allen, Eliezer M.

AU - Winer, Eric P.

AU - Lin, Nancy U.

AU - Nakabayashi, Mari

AU - Taplin, Mary Ellen

AU - Johannessen, Cory M.

AU - Garraway, Levi A.

AU - Golub, Todd R.

AU - Boehm, Jesse S.

AU - Wagle, Nikhil

AU - Getz, Gad

AU - Love, J. Christopher

AU - Meyerson, Matthew

PY - 2017/12/1

Y1 - 2017/12/1

N2 - Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

AB - Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.

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DO - 10.1038/s41467-017-00965-y

M3 - Article

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AN - SCOPUS:85032954984

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

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M1 - 1324

ER -

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Abstract

ASJC Scopus subject areas

UN SDGs

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