A harmonized meta-knowledgebase of clinical interpretations of somatic genomic variants in cancer

Alex H Wagner,Xuan Shirley Li,Brian Walsh,Melissa Haendel,Malachi Griffith,Ryan P Duren,Ethan Cerami,Subha Madhavan,O.u Sezerman ,Jeremy L Warner,Nikolaus Schultz,Núria López‐Bigas ,Kyle Ellrott,Catherine Del Vecchio Fitz,Jianjiong Gao,Mark Lawler,Michael Baudis,David Tamborero,Jacques S Beckmann,Jeremy Goecks,Gordana Raca,Susan M Mockus ,Tero Aittokallio,Beth A Pitel,Sara E Patterson ,Lynn M Schriml,Debyani Chakravarty,Olivier Elemento,Julie A Mcmurry ,Deborah Ritter ,Georgia Mayfield,Obi L Griffith,Damian Rieke ,Jordi Deu-Pons,Kilannin Krysiak,Robert R Freimuth,Rodrigo Dienstmann,Dmitriy Sonkin,Adam A Margolin

doi:10.1038/s41588-020-0603-8

Abstract

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.

Highlights

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection
We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting
Stakeholders interested in the effects of somatic cancer variants are faced with the following trade-off: (1) reconciling multiple representations and interpretations across knowledgebases; or (2) potentially omitting clinically significant interpretations that are not universally captured

Summary

Introduction

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. The Variant Interpretation for Cancer Consortium (VICC; cancervariants.org) is a Driver Project of GA4GH, established to co-develop standards for genomic data sharing (https://www.ga4gh.org/how-we-work/ driver-projects/ga4gh.org/howwework/driver-projects.html). The Association for Molecular Pathology, the American Society of Clinical Oncology and the College of American Pathologists (AMP/ ASCO/CAP) have published structured somatic variant clinical interpretation guidelines that address diagnostic, prognostic and therapeutic implications[22]. These guidelines do not provide systematic and comprehensive procedures to classify somatic variant oncogenicity, as has been published in the American College of Medical Genetics and Genomics (ACMG)/AMP guidelines[23] for pathogenicity interpretation of germline variants

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Results

Conclusion