Low-pass Whole-genome Sequencing of Circulating Cell-free DNA Demonstrates Dynamic Changes in Genomic Copy Number in a Squamous Lung Cancer Clinical Cohort

• Published in: Clinical cancer research 2019-04, Vol.25 (7), p.2254-2263
• Main Authors: Chen, Xiaoji, Chang, Ching-Wei, Spoerke, Jill M, Yoh, Kathryn E, Kapoor, Vidushi, Baudo, Charles, Aimi, Junko, Yu, Mamie, Liang-Chu, May M Y, Suttmann, Rebecca, Huw, Ling-Yuh, Gendreau, Steven, Cummings, Craig, Lackner, Mark R
• Format: Article
• Language: English
• Subjects: Biomarkers, Tumor; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Cell Line, Tumor; Circulating Tumor DNA; Cohort Studies; DNA Copy Number Variations; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Genome, Human; Genomics - methods; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Molecular Targeted Therapy; Polymorphism, Single Nucleotide; Prognosis; Sequence Analysis, DNA; Whole Genome Sequencing
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1593

We developed a method to monitor copy number variations (CNV) in plasma cell-free DNA (cfDNA) from patients with metastatic squamous non-small cell lung cancer (NSCLC). We aimed to explore the association between tumor-derived cfDNA and clinical outcomes, and sought CNVs that may suggest potential resistance mechanisms. Sensitivity and specificity of low-pass whole-genome sequencing (LP-WGS) were first determined using cell line DNA and cfDNA. LP-WGS was performed on baseline and longitudinal cfDNA of 152 patients with squamous NSCLC treated with chemotherapy, or in combination with pictilisib, a pan-PI3K inhibitor. cfDNA tumor fraction and detected CNVs were analyzed in association with clinical outcomes. LP-WGS successfully detected CNVs in cfDNA with tumor fraction ≥10%, which represented approximately 30% of the first-line NSCLC patients in this study. The most frequent CNVs were gains in chromosome 3q, which harbors the and oncogenes. The CNV landscape in cfDNA with a high tumor fraction generally matched that of corresponding tumor tissue. Tumor fraction in cfDNA was dynamic during treatment, and increases in tumor fraction and corresponding CNVs could be detected before radiographic progression in 7 of 12 patients. Recurrent CNVs, such as amplification, were enriched in cfDNA from posttreatment samples compared with the baseline, suggesting a potential resistance mechanism to pictilisib. LP-WGS offers an unbiased and high-throughput way to investigate CNVs and tumor fraction in cfDNA of patients with cancer. It may also be valuable for monitoring treatment response, detecting disease progression early, and identifying emergent clones associated with therapeutic resistance.