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

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.研究目的：明确体细胞突变与肿瘤放射应答之间的关联，是阐明放疗作用机制、开展个性化放疗实践的关键所在。本研究旨在通过靶向下一代DNA测序（targeted next-generation DNA sequencing）技术，挖掘与放射应答相关的特异性基因或分子通路。 材料与方法：本研究共纳入55例罹患各类实体瘤的患者，其肿瘤标本采用包含148个癌症相关基因的机构定制测序面板完成测序，且患者因存在可测量肿瘤接受放疗。将经放疗后肿瘤完全缓解或部分缓解且持续时间超过6个月的患者定义为放射应答者。本研究分析了148个基因中的致病性单核苷酸变异、插入/缺失突变，以及39条分子通路的突变状态与放射应答之间的关联。 研究结果：本研究共纳入17例放射应答者与38例非放射应答者，分析显示生物有效剂量（biologically effective dose, BED）与放射应答显著相关，而同步化疗则与放射应答无明显关联。未发现单个基因的突变与放射应答存在相关性。经多重比较校正后，Notch信号通路（Notch signaling pathway）的突变与放射敏感性呈显著相关（校正后P=0.094）。将生物有效剂量与Notch信号通路突变纳入logistic回归分析后，二者均与放射应答显著相关。 研究结论：本研究结果提示，Notch信号通路的体细胞突变可能与肿瘤放射敏感性相关，但该结论仍需在更大规模且同质化的队列研究中加以验证。