Targeted next-generation DNA sequencing identifies Notch signaling pathway mutation as a predictor of radiation response

Abstract

Purpose: Identifying the association between somatic mutations and the radiation response of tumor is essential for understanding the mechanisms and practicing personalized radiotherapy. The present study aimed to discover specific genes or pathways that are associated with radiation response using targeted next-generation DNA sequencing. Material and methods: Fifty-five patients with various solid tumors whose specimen were sequenced using institutional panel which includes 148 cancer-related genes and received radiotherapy for a measurable tumor were analyzed. Patients with irradiated tumors in complete or partial remission for more than 6 months were defined as responders. Association between mutations including pathogenic single nucleotide variants and insertions/deletions in the 148 genes and 39 molecular pathways and radiation response was investigated. Results: Analyzing 17 responders and 38 non-responders, biologically effective dose (BED), but not concurrent chemotherapy, was associated with radiation response. No single gene correlated with radiation response. Mutations in Notch signaling pathway were associated with radiosensitivity after correction for multiple comparison (adjusted p = .094). When BED and Notch signaling pathway mutation were tested with logistic regression, both variables were associated with radiation response. Conclusions: Our results suggest that somatic mutations in Notch signaling pathway may be related to sensitivity to radiation, although these results should be validated in a larger and more homogeneous cohort.