4. Coordinating variant interpretation knowledgebases improves clinical interpretation of genomic variants in cancers

Abstract

The promise of precision medicine in which a cancer patient's treatment is tailored to their specific cancer variants requires concise, standardized, and searchable clinical interpretations: biomarker-disease associations that provide clinical value. While many institutions curate interpretations for clinically relevant cancer variants, these efforts are siloed and non-interoperable. Through the Global Alliance for Genomics and Health (GA4GH), we formed a Variant Interpretation for Cancer Consortium (VICC, cancervariants.org). We have evaluated six established sources of cancer variant interpretations hosted by members of the consortium, and compared the coverage of the biomedical literature across them. We found that from 6034 publications across the collective, 86% were unique (by PubMed ID). This illustrates both the value to be gained from aggregating the knowledge of these resources and implies an enormity of biomedical literature describing cancer variants that is not yet queryable. We have integrated guidelines and ontologies describing genes, variants, diseases, drugs, and evidence to create a framework and resource for sharing these interpretations. In the process, we collectively established a set of minimum elements required for describing a cancer variant interpretation, and used this to guide harvesting and harmonizing knowledge from these founding resources. Our results demonstrate that the knowledge from the constituent sources of the VICC are highly heterogeneous across every element defining these interpretations (genes/variants, drugs, diseases, evidence). We have developed a harmonized database and an alpha-stage web interface for exploring and querying this breadth of knowledge, and demonstrated improved clinical interpretation of patients from cancer cohorts (TCGA, GENIE)