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

View ORCID ProfileAlex H Wagner, Brian Walsh, Georgia Mayfield, David Tamborero, View ORCID ProfileDmitriy Sonkin, View ORCID ProfileKilannin Krysiak, Jordi Deu Pons, Ryan Duren, Jianjiong Gao, Julie McMurry, Sara Patterson, Catherine Del Vecchio Fitz, Ozman Ugur Sezerman, Jeremy Warner, Damian T Rieke, Tero Aittokallio, Ethan Cerami, Deborah Ritter, Lynn M Schriml, Melissa Haendel, Gordana Raca, Subha Madhavan, View ORCID ProfileMichael Baudis, View ORCID ProfileJacques S Beckmann, Rodrigo Dienstmann, Debyani Chakravarty, Xuan Shirley Li, View ORCID ProfileSusan Mockus, Olivier Elemento, Nikolaus Schultz, Nuria Lopez-Bigas, Mark Lawler, Jeremy Goecks, View ORCID ProfileMalachi Griffith, View ORCID ProfileObi L Griffith, Adam Margolin
doi: https://doi.org/10.1101/366856
Alex H Wagner
1Washington University School of Medicine, St. Louis, MO, USA
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Brian Walsh
2Oregon Health and Science University, Portland, OR, USA
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Georgia Mayfield
2Oregon Health and Science University, Portland, OR, USA
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David Tamborero
3Institute for Research in Biomedicine, Barcelona, Spain
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Dmitriy Sonkin
4National Cancer Institute, Rockville, MD, USA
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Kilannin Krysiak
1Washington University School of Medicine, St. Louis, MO, USA
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Jordi Deu Pons
3Institute for Research in Biomedicine, Barcelona, Spain
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Ryan Duren
5MolecularMatch, Houston, TX, USA
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Jianjiong Gao
6Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Julie McMurry
2Oregon Health and Science University, Portland, OR, USA
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Sara Patterson
7The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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Catherine Del Vecchio Fitz
8Dana-Farber Cancer Institute, Boston, MA, USA
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Ozman Ugur Sezerman
9Acibadem University, Istanbul, Turkey
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Jeremy Warner
10Vanderbilt University, Nashville, TN, USA
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Damian T Rieke
11Charité University Medicine Berlin, Berlin, Germany
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Tero Aittokallio
12University of Helsinki and FIMM, Helsinki, Finland
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Ethan Cerami
8Dana-Farber Cancer Institute, Boston, MA, USA
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Deborah Ritter
13Baylor College of Medicine, Houston, TX
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Lynn M Schriml
14University of Maryland School of Medicine, Baltimore, MD, USA
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Melissa Haendel
2Oregon Health and Science University, Portland, OR, USA
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Gordana Raca
15University of Southern California, Los Angeles, CA, USA
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Subha Madhavan
16Georgetown University Medical Center, Washington D.C., USA
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Michael Baudis
17University of Zurich, Zurich, Switzerland
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Jacques S Beckmann
18University of Lausanne, Lausanne, Switzerland
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Rodrigo Dienstmann
19Vall d’Hebron Institute of Oncology, Barcelona, Spain
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Debyani Chakravarty
6Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Xuan Shirley Li
5MolecularMatch, Houston, TX, USA
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Susan Mockus
7The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
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Olivier Elemento
20Weill Cornell Medicine, New York, NY, USA
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Nikolaus Schultz
6Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Nuria Lopez-Bigas
3Institute for Research in Biomedicine, Barcelona, Spain
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Mark Lawler
21Queen’s University Belfast, Belfast, Northern Ireland
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Jeremy Goecks
2Oregon Health and Science University, Portland, OR, USA
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Malachi Griffith
1Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: mgriffit@wustl.edu obigriffith@wustl.edu
Obi L Griffith
1Washington University School of Medicine, St. Louis, MO, USA
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  • For correspondence: mgriffit@wustl.edu obigriffith@wustl.edu
Adam Margolin
2Oregon Health and Science University, Portland, OR, USA
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ABSTRACT

Precision oncology relies on the accurate discovery and interpretation of genomic variants to enable individualized therapy selection, diagnosis, or prognosis. However, knowledgebases containing clinical interpretations of somatic cancer variants are highly disparate in interpretation content, structure, and supporting primary literature, reducing consistency and impeding consensus when evaluating variants and their relevance in a clinical setting. With the cooperation of experts of the Global Alliance for Genomics and Health (GA4GH) and of six prominent cancer variant knowledgebases, we developed a framework for aggregating and harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations covering 3,437 unique variants in 415 genes, 357 diseases, and 791 drugs. We demonstrated large gains in overlapping terms between resources across variants, diseases, and drugs as a result of this harmonization. We subsequently demonstrated improved matching between patients of the GENIE cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 34% to 57% in aggregate. We developed an open and freely available web interface for exploring the harmonized interpretations from these six knowledgebases at search.cancervariants.org.

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Posted July 11, 2018.
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A harmonized meta-knowledgebase of clinical interpretations of cancer genomic variants
Alex H Wagner, Brian Walsh, Georgia Mayfield, David Tamborero, Dmitriy Sonkin, Kilannin Krysiak, Jordi Deu Pons, Ryan Duren, Jianjiong Gao, Julie McMurry, Sara Patterson, Catherine Del Vecchio Fitz, Ozman Ugur Sezerman, Jeremy Warner, Damian T Rieke, Tero Aittokallio, Ethan Cerami, Deborah Ritter, Lynn M Schriml, Melissa Haendel, Gordana Raca, Subha Madhavan, Michael Baudis, Jacques S Beckmann, Rodrigo Dienstmann, Debyani Chakravarty, Xuan Shirley Li, Susan Mockus, Olivier Elemento, Nikolaus Schultz, Nuria Lopez-Bigas, Mark Lawler, Jeremy Goecks, Malachi Griffith, Obi L Griffith, Adam Margolin
bioRxiv 366856; doi: https://doi.org/10.1101/366856
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A harmonized meta-knowledgebase of clinical interpretations of cancer genomic variants
Alex H Wagner, Brian Walsh, Georgia Mayfield, David Tamborero, Dmitriy Sonkin, Kilannin Krysiak, Jordi Deu Pons, Ryan Duren, Jianjiong Gao, Julie McMurry, Sara Patterson, Catherine Del Vecchio Fitz, Ozman Ugur Sezerman, Jeremy Warner, Damian T Rieke, Tero Aittokallio, Ethan Cerami, Deborah Ritter, Lynn M Schriml, Melissa Haendel, Gordana Raca, Subha Madhavan, Michael Baudis, Jacques S Beckmann, Rodrigo Dienstmann, Debyani Chakravarty, Xuan Shirley Li, Susan Mockus, Olivier Elemento, Nikolaus Schultz, Nuria Lopez-Bigas, Mark Lawler, Jeremy Goecks, Malachi Griffith, Obi L Griffith, Adam Margolin
bioRxiv 366856; doi: https://doi.org/10.1101/366856

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