RT Journal Article
SR Electronic
T1 The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 233205
DO 10.1101/233205
A1 Oliver A. Zill
A1 Kimberly C. Banks
A1 Stephen R. Fairclough
A1 Stefanie A. Mortimer
A1 James V. Vowles
A1 Reza Mokhtari
A1 David R. Gandara
A1 Philip C. Mack
A1 Justin I. Odegaard
A1 Rebecca J. Nagy
A1 Arthur M. Baca
A1 Helmy Eltoukhy
A1 Darya I. Chudova
A1 Richard B. Lanman
A1 AmirAli Talasaz
YR 2017
UL http://biorxiv.org/content/early/2017/12/12/233205.abstract
AB Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity pose analytical challenges. We present the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC), with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. To facilitate interpretation of this added complexity, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality. Upon applying these methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations, in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel alterations and parallel evolution, was common in the cfDNA cohort and was enriched in patients with targetable driver alterations. Together these retrospective analyses of a large set of cfDNA deep-sequencing data reveal subclonal structures and emerging resistance in advanced solid tumors.