Mutation load estimation model as a predictor of the response to cancer immunotherapy

Abstract

The determination of the mutation load, a total number of nonsynonymous point mutations, by whole-exome sequencing was shown to be useful in predicting the treatment responses to cancer immunotherapy. However, this technique is expensive and time-consuming, which hampers its application in clinical practice. Therefore, the objective of this study was to construct a mutation load estimation model for lung adenocarcinoma, using a small set of genes, as a predictor of the immunotherapy treatment response. Using the somatic mutation data downloaded from The Cancer Genome Atlas (TCGA) database, a computational framework was developed. The estimation model consisted of only 24 genes, used to estimate the mutation load in the independent validation cohort precisely (R² = 0.7626). Additionally, the estimated mutation load can be used to identify the patients with durable clinical benefits, with 85% sensitivity, 93% specificity, and 89% accuracy, indicating that the model can serve as a predictive biomarker for cancer immunotherapy treatment response. Furthermore, our analyses demonstrated the necessity of the cancer-specific models by the constructed melanoma and colorectal models. Since most genes in the lung adenocarcinoma model are not currently included in the sequencing panels, a customized targeted sequencing panel can be designed with the selected model genes to assess the mutation load, instead of whole-exome sequencing or the currently used panel-based methods. Consequently, the cost and time required for the assessment of mutation load may be considerably decreased, which indicates that the presented model is a more cost-effective approach to cancer immunotherapy response prediction in clinical practice.