Ling Yang1, Xiaoyan Zhang2, Matthew MacKay3, Jonathan Foox3, Qiang Hou2, Xiaoli Zheng2, Rongjing Zhou4, Ming Huang2, Zhao Jing5, Christopher E Mason6, Shixiu Wu7. 1. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. 2. Hangzhou Cancer Institute, Hangzhou Cancer Hospital, Hangzhou, China. 3. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York. 4. Department of Pathology, Hangzhou Cancer Hospital, Hangzhou, China. 5. Hangzhou Cancer Institute, Hangzhou Cancer Hospital, Hangzhou, China; Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China. 6. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York; The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York; The Feil Family Brain and Mind Research Institute (BMRI), New York, New York. 7. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. Electronic address: wushixiu@zju.edu.cn.
Abstract
PURPOSE: The majority (70%) of the esophageal squamous cell carcinoma (ESCC) cases in the world occur in China, where radiation therapy is the most common treatment. Yet the majority of ESCC patients still relapse. METHODS AND MATERIALS: To better understand the genetic basis of radiation therapy resistance for ESCC, we performed longitudinal, whole-exome sequencing throughout radiation therapy on 42 patient tumor samples, including single-cell whole-exome sequencing for 147 cells for 2 patients. RESULTS: Significant allelic changes were observed during clinical irradiation, with 42 recurrent radioresponsive genes (sensitive and resistant) identified in multiple patients, including NOTCH1, MAML3, CDKN2A, NFE2L2, GAS2L2, OBSCN and TP53, with the last 3 genes implicated as radioresponsive in both bulk and single-cell whole-exome sequencing. Most (37/42) radioresponsive genes showed regional variegation in both radioresistant and radiosensitive mutations, with a paucity of resistant-only mutations (2.5%). A subset of sensitive mutations in 10 genes and resistant mutations in 18 genes defined a significantly improved prognosis and the shortest time for locoregional recurrence, respectively, indicating possible clinical utility. We also confirmed these significant mutational signatures in orthogonal Cancer Genome Atlas ESCC cohorts. CONCLUSIONS: Overall, our results quantify the allelic shifts underlying radioresponse in bulk and single-cell ESCC exomes for the first time, provide a temporal resolution to such mutational dynamics, and offer new therapeutic target genes and loci for esophageal and potentially other cancers.
RCT Entities:
PURPOSE: The majority (70%) of the esophageal squamous cell carcinoma (ESCC) cases in the world occur in China, where radiation therapy is the most common treatment. Yet the majority of ESCC patients still relapse. METHODS AND MATERIALS: To better understand the genetic basis of radiation therapy resistance for ESCC, we performed longitudinal, whole-exome sequencing throughout radiation therapy on 42 patienttumor samples, including single-cell whole-exome sequencing for 147 cells for 2 patients. RESULTS: Significant allelic changes were observed during clinical irradiation, with 42 recurrent radioresponsive genes (sensitive and resistant) identified in multiple patients, including NOTCH1, MAML3, CDKN2A, NFE2L2, GAS2L2, OBSCN and TP53, with the last 3 genes implicated as radioresponsive in both bulk and single-cell whole-exome sequencing. Most (37/42) radioresponsive genes showed regional variegation in both radioresistant and radiosensitive mutations, with a paucity of resistant-only mutations (2.5%). A subset of sensitive mutations in 10 genes and resistant mutations in 18 genes defined a significantly improved prognosis and the shortest time for locoregional recurrence, respectively, indicating possible clinical utility. We also confirmed these significant mutational signatures in orthogonal Cancer Genome Atlas ESCC cohorts. CONCLUSIONS: Overall, our results quantify the allelic shifts underlying radioresponse in bulk and single-cell ESCC exomes for the first time, provide a temporal resolution to such mutational dynamics, and offer new therapeutic target genes and loci for esophageal and potentially other cancers.