Assessing the validity of driver gene identification tools for targeted genome sequencing data

Motivation: Most cancer driver gene identification tools have been developed for whole-exome sequencing data. Targeted sequencing is a popular alternative to whole-exome sequencing for large cancer studies due to its greater depth at a lower cost per tumor. Unlike whole-exome sequencing, targeted sequencing only enables mutation calling for a selected subset of genes. Whether existing driver gene identification tools remain valid in that context has not previously been studied. Results: We evaluated the validity of seven popular driver gene identification tools when applied to targeted sequencing data. Based on whole-exome data of 14 different cancer types from TCGA, we constructed matching targeted datasets by keeping only the mutations overlapping with the pan-cancer MSK-IMPACT panel and, in the case of breast cancer, also the breast-cancer-specific B-CAST panel. We then compared the driver gene predictions obtained on whole-exome and targeted mutation data for each of the seven tools. Differences in how the tools model background mutation rates were the most important determinant of their validity on targeted sequencing data. Based on our results, we recommend OncodriveFML, OncodriveCLUSTL, 20/20+, dNdSCv, and ActiveDriver for driver gene identification in targeted sequencing data, whereas MutSigCV and DriverML are best avoided in that context. Availability and implementation: Code for the analyses is available at https://github.com/SchmidtGroupNKI/TGSdrivergene_validity.