Journal Article

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

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

2017

Overview

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. Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/69 / 692/4028/67 / Antigens, Neoplasm - genetics / Blood / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - secondary / Cell-Free Nucleic Acids - blood / Cell-Free Nucleic Acids - genetics / Copy number / Deoxyribonucleic acid / DNA / DNA Mutational Analysis / DNA sequencing / DNA, Neoplasm - blood / DNA, Neoplasm - genetics / Exome Sequencing - methods / Exome Sequencing - statistics & numerical data / Female / Gene Dosage / Genomes / Humanities and Social Sciences / Humans / Identification methods / Male / Metastases / Metastasis / multidisciplinary / Mutation / Neoantigens / Neoplasm Metastasis - drug therapy / Neoplasm Metastasis - genetics / Patients / Prospective Studies / Prostate / Prostate cancer / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - secondary / Science / Science (multidisciplinary) / Software / Tumors