Sequential Whole Exome Sequencing Reveals Somatic Mutations Associated with Platinum Response in NSCLC

Ao-Xiang Guo; Fan Xiao; Wei-Hua Shao; Yan Zhan; Le Zhang; Jing Xiong; Yang Gao; Ji-Ye Yin

doi:10.2147/OTT.S254747

Sequential Whole Exome Sequencing Reveals Somatic Mutations Associated with Platinum Response in NSCLC

Onco Targets Ther. 2020 Jul 3:13:6485-6496. doi: 10.2147/OTT.S254747. eCollection 2020.

Authors

Ao-Xiang Guo^{1

2

3

4}, Fan Xiao^{1

2

3

4}, Wei-Hua Shao^{1

2

3

4}, Yan Zhan^{1

2

3

4}, Le Zhang⁵, Jing Xiong⁶, Yang Gao^{1

2

7

8}, Ji-Ye Yin^{1

2

3

4

9}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.
² Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, People's Republic of China.
³ Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha 410078, People's Republic of China.
⁴ National Clinical Research Center for Geriatric Disorders, Changsha 410008, Hunan, People's Republic of China.
⁵ Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
⁶ Department of Gynaecology and Obstetrics, The Second Xiangya Hospital, Central South University, Changsha 410011, People's Republic of China.
⁷ Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha 410078, People's Republic of China.
⁸ Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis & Treatment, Changsha 410078, People's Republic of China.
⁹ Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Changsha 410078, People's Republic of China.

Abstract

Purpose: Resistance is one of the main limitations of successful platinum treatment in non-small-cell lung cancer (NSCLC) patients. In this study, we aimed to identify somatic mutations associated with platinum response.

Patients and methods: A total of 57 patients who received platinum-based chemotherapy only and 13 patients who received neoadjuvant chemotherapy (NAC) were enrolled. Somatic mutations were obtained from targeted and whole exome sequencing (WES).

Results: Somatic mutations in a total of 225 genes were observed. Nonsynonymous variants in EGFR, TTN, TP53 and KRAS, and copy number variations (SCNVs) in chromosome 8q24.3 and 22q11.21 were identified to be associated with platinum response. Based on these mutations, the mutational signature associated with the failure of DNA double-strand break and calcium signaling pathways were identified to be associated with platinum response. Besides, we observed a decrease in tumor mutational burden after chemotherapy. We also evaluated the mutation spectrum consistency between cell-free DNA (cfDNA) and tissue DNA. Somatic mutations detected in cfDNA were consistent with that in tDNA, which indicated that plasma might be used for somatic mutation detection.

Conclusion: These results support that somatic mutations can affect platinum drug response and provide potential clinical biomarkers for NSCLC treatment.

Keywords: NSCLC; TP53; TTN; cfDNA; platinum.