OncoKB: A Precision Oncology Knowledge Base

Abstract

Executive Summary PURPOSE With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

HER kinase inhibition in patients with HER2- and HER3-mutant cancers

“…For gene level analysis, select genes within our targeted 341/410 MSK-IMPACT panel involved in the RTK/RAS/RAF, PIK3CA/AKT/MTOR, and cell cycle checkpoint pathways were selected using the KEGG pathway database 43 . For pathway level analysis, only potentially oncogenic alterations in the selected genes were included and determined to be oncogenic by OncoKB (version September 2017), a curated knowledge base of the oncogenic effects and treatment implications of mutations and cancer genes (oncokb.org 44 ).…”

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…Oncogenic relevance was assessed using OncoKB, a knowledgebase for the oncogenic effects of cancer genes that is manually curated by researchers and physicians at Memorial Sloan Kettering (Chakravarty et al, 2017). More precisely, a mutation is counted and included in the diagrams if (1) it has been reported 4 or more times in COSMIC (Forbes et al, 2011), or (2) it has been labeled as oncogenic, or likely oncogenic, in OncoKB.…”

Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community‐driven standards

“…The PSWG has defined a set of pediatric cancer genes in specific childhood tumor types, and has identified and prioritized variants in disease‐gene pairs using Mastermind, a literature mining search tool (https://mastermind.genomenon.com/). A gene‐disease search in Mastermind produces a list of variants, and these are prioritized based on the following: (1) overall absence of curated data in CIViC, (2) the number of article hits against the Mastermind search, (3) the number of hits against a PubMed search, and (4) review of variants in pediatric‐relevant datasets (Chakravarty et al., 2017; Ma et al., 2018). The variants are discussed and vetted with experts on the WG call.…”

“…Currently, there are multiple platforms and portals hosting cancer variant data with a clinical focus, including OncoKB, CanDL, My Cancer Genome, The Jackson Laboratories Clinical Knowledgebase, and ClinVar (Chakravarty et al., 2017; Damodaran et al., 2015; Landrum et al., 2016b; Patterson et al., 2016; Swanton, 2012). This speaks to the need for coordinated efforts such as that presented here to define and relate central data elements.…”