VONC: A solution for the clinical assessment of somatic genomic alterations.

Abstract

e13155 Background: Next generation sequencing (NGS) technology is transforming the diagnosis and treatment of cancer. However, the massive scale of data has overwhelmed pathologists who need streamlined tools to process this data, automate report generation and minimize human errors. Methods: We developed the Variant interpretation station for ONCology, VONC, as an end-to-end solution for moving from NGS whole exome and transcriptome data to actionable clinical reports that support cancer diagnosis, prognosis, and personalized treatment strategies for solid and hematologic malignancies. Results: VONC integrates all steps for moving from raw NGS data, variant calling and LIMS, to comprehensive annotation of variants. The main functional feature of VONC is a transparent process that effectively combines automated and expert curation to identify clinically relevant and actionable driver variants. VONC also enables efficient management of multi-group, -role, -system and -site curation processes. In contrast to current tools, VONC handles all somatic and constitutional genomic alterations including SNV, indel, CNV, fusion, splicing, and gene expression. Key data sources include 1) 350,000 variants for 50 tumor types across 57,000 sequenced cancer patients; 2) variant frequencies estimated from 1.5M cancer patients; 3) expert curated literature evidence from 16,818 papers covering 26,496 alterations spanning 2,448 cancer driver genes; and 4) curated database of FDA-approved drugs and recruiting clinical trials. VONC presents a prioritized list of variants in oncogenes and tumor suppressors through functional (literature-based) and structure-based (hotspots) algorithms. This is coupled to all supporting information necessary for clinical decision making. Curators can quickly screen variant type, QC metrics, and frequency in sequencing cohorts of cancer patients as well as healthy subjects. Within minutes, variants can be triaged and annotated with FDA approved, NCCN guidelines reported, or literature supported therapeutics, including resistance and contraindicated. Conclusions: VONC is a clinically-ready tool with an intuitive end-user interface tailored for the rapid assessment of variants in cancer patients, to facilitate personalized cancer medicine in a high-throughput laboratory.