Lung Neoplasms study with Targeted-Capture, WGS data on dbGaP (143 participants)

phs003570 — Detecting and Subtyping Lung Cancer Through Analysis of Circulating Tumor    DNA

<p>Small cell lung cancer (SCLC) is among the most aggressive tumors with poor clinical outcomes. Tumors are rarely resected, which is a major barrier to molecular profiling of tumor tissue; therefore, non-invasive approaches using circulating tumor DNA (ctDNA) from liquid biopsies are needed to help advance research and clinical care for patients with SCLC. We developed a targeted capture panel that profiles SCLC genes and transcriptional regulation sites, including transcription start sites (TSS) and transcription factor binding sites (TFBS). This is a single assay that detects genomic mutations and transcriptional regulation activity based on ctDNA fragment patterns reflecting epigenetic nucleosomal positions. We applied this assay to sequence patient-derived xenograft (PDX) and patient plasma samples. We also performed whole genome sequencing (WGS) for a subset of the PDX plasma samples to validate the capture data. We developed new algorithms to quantify activity of key SCLC marker genes of <a href="https://www.ncbi.nlm.nih.gov/gene/429">ASCL1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/4760">NEUROD1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/25833">POU2F3</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/474">ATOH1</a> and to classify SCLC subtypes based on activity of these markers. Furthermore, we developed a model to classify SCLC from non-small cell lung cancer (NSCLC), which has potential important applications for monitoring transdifferentiation and tumor plasticity.</p>