Genomic Landscape of Cell-Free DNA in Patients with Colorectal Cancer

• Published in: Cancer discovery Vol. 8; no. 2; pp. 164 - 173
• Main Authors: Strickler, John H, Loree, Jonathan M, Ahronian, Leanne G, Parikh, Aparna R, Niedzwiecki, Donna, Pereira, Allan Andresson Lima, McKinney, Matthew, Korn, W Michael, Atreya, Chloe E, Banks, Kimberly C, Nagy, Rebecca J, Meric-Bernstam, Funda, Lanman, Richard B, Talasaz, AmirAli, Tsigelny, Igor F, Corcoran, Ryan B, Kopetz, Scott
• Format: Journal Article
• Language: English
• Published: United States 01.02.2018
• Subjects: Biomarkers, Tumor; Cell-Free Nucleic Acids; Clonal Evolution - genetics; Cohort Studies; Colorectal Neoplasms - blood; Colorectal Neoplasms - genetics; DNA, Neoplasm; ErbB Receptors - genetics; Genome-Wide Association Study; Genomics - methods; Humans; Mutation
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-17-1009

"Liquid biopsy" approaches analyzing cell-free DNA (cfDNA) from the blood of patients with cancer are increasingly utilized in clinical practice. However, it is not yet known whether cfDNA sequencing from large cohorts of patients with cancer can detect genomic alterations at frequencies similar to those observed by direct tumor sequencing, and whether this approach can generate novel insights. Here, we report next-generation sequencing data from cfDNA of 1,397 patients with colorectal cancer. Overall, frequencies of genomic alterations detected in cfDNA were comparable to those observed in three independent tissue-based colorectal cancer sequencing compendia. Our analysis also identified a novel cluster of extracellular domain (ECD) mutations in , mediating resistance by blocking binding of anti-EGFR antibodies. Patients with ECD mutations displayed striking tumor heterogeneity, with 91% harboring multiple distinct resistance alterations (range, 1-13; median, 4). These results suggest that cfDNA profiling can effectively define the genomic landscape of cancer and yield important biological insights. This study provides one of the first examples of how large-scale genomic profiling of cfDNA from patients with colorectal cancer can detect genomic alterations at frequencies comparable to those observed by direct tumor sequencing. Sequencing of cfDNA also generated insights into tumor heterogeneity and therapeutic resistance and identified novel ectodomain mutations. .