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作者

Li Li Shanshan Tang Jiani C Yin Lihua Dong Zhe Yang Yueping Liu Jie Ma Pengyu Chang Jiaohui Pang Hua Bao Dianbin Mu Xiaoli Zheng Reyida Aishajiang Kewen He Shaotong Zhang Meng Ni Xue Wu Xiaonan Wang Yang Shao Jun Wang Hong Ge Jinming Yu Shuanghu Yuan

作者单位

Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, Jinan, Shandong, China. Electronic address: sdyujinming@16 Affiliations ¹ Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, Jinan, Shandong, China. ² Nanjing Geneseeq Technology Inc, Nanjing, Jiangsu, China. ³ Department of Radiation Oncology & Therapy, Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, China. ⁴ Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China. ⁵ Department of Pathology, Fourth Hospital of Hebei Medical University, Hebei, China. ⁶ Department of Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China. ⁷ Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. ⁸ Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China. ⁹ Department of Cardiology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. ¹⁰ Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China. ¹¹ Nanjing Geneseeq Technology Inc, Nanjing, Jiangsu, China com. ¹⁵ Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong, Jinan, Shandong, China Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: yuanshuanghu@sina.com. com. ¹⁴ Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: yang.shao@geneseeq.com. ¹² Department of Radiotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: wangjunzr@16 com. ¹³ Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: gehong616@12

刊名

International journal of radiation oncology, biology, physics

年份

2022

卷号

Vol.112 No.5

页码

1165-1176

ISSN

1879-355X

关键词

SEVERE RADIATION PNEUMONITIS GENETIC-VARIANTS ATM POLYMORPHISMS RAS ONCOGENES RADIOTHERAPY ASSOCIATION RESISTANCE CARCINOMA PATHWAYS COMMON

摘要

Purpose: Although definitive chemoradiation therapy remains the most effective treatment modality in limited stage small cell lung cancer , some patients progress quickly or develop serious radiation-induced thoracic toxicity . Molecular correlates of response to dCRT remain to be explored. Methods and materials: Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation t...更多

Purpose: Although definitive chemoradiation therapy remains the most effective treatment modality in limited stage small cell lung cancer , some patients progress quickly or develop serious radiation-induced thoracic toxicity . Molecular correlates of response to dCRT remain to be explored. Methods and materials: Genomic profiling was performed retrospectively on 231 patients with limited-stage SCLC treated with dCRT between 2015 and 2019 using a customized panel covering cancer and radiation therapy response-related genes. Exploratory associations of progression-free survival, overall survival, and RITT with clinical features, tumor genetics, genomic and molecular pathway alterations, and single nucleotide polymorphisms were conducted. Results: In addition to the common SCLC genes, such as TP53, RB1, and NOTCH1/2, potentially actionable mutations in EGFR, KRAS, and BRCA1/2 were among the top alterations in the cohort. At the single-gene level, CDK4 and GATA6 alterations were independent predictors of poor survival by multivariate analysis. At the genomic level, high tumor mutational burden was strongly associated with favorable survival outcome. Pathway-level analysis showed that activating mutations in the MAPK/ERK pathway genes, particularly those in EGFR/ERBB2, correlated with poor survival. Combined analysis enabled optimized risk stratification of post-dCRT survival. On the other hand, our study also confirmed that single nucleotide polymorphisms in MTHFR, CYP2B6, NQO1, and LIG4 were risk alleles of high-grade RITT. Remarkably, somatic loss-of-function mutations in the DNA damage repair pathway genes were associated with increased risk of high-grade RITT, particularly pneumonitis, which likely reflect a complex interplay between the tumor and its immune microenvironment. Conclusions: Taken together, by examining the mutational landscape of a large cohort of limited-stage SCLC, we identified novel molecular predictors of survival and RITT. Our findings also implicate several key molecular pathways, including the MAPK/ERK and DNA damage repair pathways, in the regulation of dCRT response.收起

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