Standardized and Genome-Wide Clinical Interpretation of Complex Genotypes for Cancer Precision Medicine

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Project Summary/Abstract High-throughput molecular profiling technologies have allowed the systematic identification of molecular drivers of cancer for most major tumor types. Clinical and functional studies have correlated these drivers with patient outcomes and helped develop targeted therapies. However, maintaining current and comprehensive interpretations of the clinical significance of variants represents a major bottleneck. To address this challenge, the Clinical Interpretations of Variants in Cancer knowledgebase (CIViC; ​civicdb.org​) was created to provide a knowledge repository and sophisticated curation interface for expert-crowdsourcing the curation of actionable cancer variants. Importantly, all data are made freely available with a public domain license, daily and monthly data freezes, and public API. This has allowed widespread adoption of CIViC variant interpretations into many research tools for variant annotation as well as commercial and non-commercial report generation workflows. To date, these have focused predominantly on small mutations, detected through targeted sequencing panels, and assumed a single-target-to-single-therapy paradigm. As sequencing costs decrease, whole genome, transcriptome, and epigenome approaches will replace these targeted methods. This will allow increasingly unbiased assay of molecular alterations of most types (large and small) and will simultaneously replace many traditional cytogenetic assays. It will also dramatically increase the number of variants of potential and unknown clinical significance. Furthermore, our understanding has evolved to recognize that spatial and temporal tumor heterogeneity result in complex tumor genotypes of collaborating mutations that will require a more sophisticated decision support framework. To address these challenges, the CIViC data model will be extended to support: new frameworks for representing complex tumor genotypes; ACMG and AMP guidelines for both germline and somatic variant curation; and new evidence codes for assessing somatic variant oncogenicity. New user interfaces will be developed to support curation, browsing and searching of these features. Clinical collaborations will be extended to: (a) develop a distributable clinical-grade (CLIA-certified) analysis platform for comprehensive genomic profiling of patient samples using whole-genome sequencing; (b) support standardized somatic variant curation through the ClinGen Somatic Working group; and (c) integrate CIViC reports into the Personalized Oncogenomics (POG) trial. The proposal will address several key challenges including: 1) understanding the importance of integrating germline annotations with somatic cancer variant interpretations; 2) determining if a whole genome approach can replace existing targeted sequencing panels and cytogenetic assays; and 3) assessing the impact of a public variant interpretation knowledgebase on clinical decisions at molecular tumor board meetings. Finally, community outreach and training will be performed to develop online workshops, improve internship opportunities, and increase interaction with medical genetics fellows to train the next-generation of researchers in precision medicine informatics.