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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.

SUBMITTER: Adalsteinsson VA 

PROVIDER: S-EPMC5673918 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Adalsteinsson Viktor A VA   Ha Gavin G   Freeman Samuel S SS   Choudhury Atish D AD   Stover Daniel G DG   Parsons Heather A HA   Gydush Gregory G   Reed Sarah C SC   Rotem Denisse D   Rhoades Justin J   Loginov Denis D   Livitz Dimitri D   Rosebrock Daniel D   Leshchiner Ignaty I   Kim Jaegil J   Stewart Chip C   Rosenberg Mara M   Francis Joshua M JM   Zhang Cheng-Zhong CZ   Cohen Ofir O   Oh Coyin C   Ding Huiming H   Polak Paz P   Lloyd Max M   Mahmud Sairah S   Helvie Karla K   Merrill Margaret S MS   Santiago Rebecca A RA   O'Connor Edward P EP   Jeong Seong H SH   Leeson Rachel R   Barry Rachel M RM   Kramkowski Joseph F JF   Zhang Zhenwei Z   Polacek Laura L   Lohr Jens G JG   Schleicher Molly M   Lipscomb Emily E   Saltzman Andrea A   Oliver Nelly M NM   Marini Lori L   Waks Adrienne G AG   Harshman Lauren C LC   Tolaney Sara M SM   Van Allen Eliezer M EM   Winer Eric P EP   Lin Nancy U NU   Nakabayashi Mari M   Taplin Mary-Ellen ME   Johannessen Cory M CM   Garraway Levi A LA   Golub Todd R TR   Boehm Jesse S JS   Wagle Nikhil N   Getz Gad G   Love J Christopher JC   Meyerson Matthew M  

Nature communications 20171106 1


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,  ...[more]

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