Knowledge bases and software support for variant interpretation in precision oncology

Abstract

Precision oncology is a rapidly evolving interdisciplinary medical specialty. Comprehensive cancer panels are becoming increasingly available at pathology departments worldwide, creating the urgent need for scalable cancer variant annotation and molecularly informed treatment recommendations. A wealth of mainly academia-driven knowledge bases calls for software tools supporting the multi-step diagnostic process. We derive a comprehensive list of knowledge bases relevant for variant interpretation by a review of existing literature followed by a survey among medical experts from university hospitals in Germany. In addition, we review cancer variant interpretation tools, which integrate multiple knowledge bases. We categorize the knowledge bases along the diagnostic process in precision oncology and analyze programmatic access options as well as the integration of knowledge bases into software tools. The most commonly used knowledge bases provide good programmatic access options and have been integrated into a range of software tools. For the wider set of knowledge bases, access options vary across different parts of the diagnostic process. Programmatic access is limited for information regarding clinical classifications of variants and for therapy recommendations. The main issue for databases used for biological classification of pathogenic variants and pathway context information is the lack of standardized interfaces. There is no single cancer variant interpretation tool that integrates all identified knowledge bases. Specialized tools are available and need to be further developed for different steps in the diagnostic process.

Keywords: HiGHmed; cancer therapy; data integration; molecular tumor board; personalized medicine.

Figure 1

Overview of the diagnostic process in precision oncology. Within this process, knowledge bases can be attributed to the three main diagnostic steps biological classification of a variant, clinical classification and knowledge bases supporting therapy recommendations. Semi-automatic or manual literature search supports the entire process. The diagnostic process is performed by an interdisciplinary team of physicians and scientists. The exact composition and responsibilities within the team vary between university centers.

Figure 2

Survey results and tool integration for KBs. We report the overall fraction of survey participants who responded to use the KBs. The individual responses can be found in the supplementary data. We also report the number of citations per year according to Google Scholar. The right matrix indicates which KBs are accessible through each cancer variant interpretation tool.