Abstract
Widespread precision oncology, where all patients with advanced cancer undergo molecular profiling (most commonly through next generation sequencing [NGS]), is currently limited by cost and technical challenges. Tissue based approaches must be compatible with small archived specimens and may require rebiopsy, while cell free DNA (cfDNA) approaches typically employ ultra-deep sequencing at a limited number of loci given the need to assess samples with tumor contents <1% and the inability to estimate tumor content a priori.
Here, through in vitro and in silico dilution experiments and profiling of a cohort of patients with metastatic cancer, we propose a pan-cancer, rapid, ultra-low coverage (~0.005-0.1x) whole genome sequencing (WGS) approach capable of identifying targetable copy number alterations (CNAs) and genome-wide copy number profiles from plasma cfDNA. This approach infers both broad and focal somatic copy number alterations from effective coverage as low as 0.005x and through a novel cfDNA tumor content estimation algorithm, can be used to guide additional precision medicine NGS workups. Our approach identified therapeutically relevant CNAs in 13/52 (25%) patient plasma cfDNA samples, and when combined with targeted multiplexed PCR-based NGS of the same cfDNA (at effective target coverage as low as 25x), enabled comprehensive assessment of somatic alterations in cfDNA from these patients. Overall, this approach holds promise as a possible screening strategy to guide precision medicine profiling approaches for patients
