Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma

Ting Yan; Heyang Cui; Yong Zhou; Bin Yang; Pengzhou Kong; Yingchun Zhang; Yiqian Liu; Bin Wang; Yikun Cheng; Jiayi Li; Shixing Guo; Enwei Xu; Huijuan Liu; Caixia Cheng; Ling Zhang; Ling Chen; Xiaofei Zhuang; Yu Qian; Jian Yang; Yanchun Ma; Hongyi Li; Fang Wang; Jing Liu; Xuefeng Liu; Dan Su; Yan Wang; Ruifang Sun; Shiping Guo; Yaoping Li; Xiaolong Cheng; Zhihua Liu; Qimin Zhan; Yongping Cui

doi:10.1038/s41467-019-09255-1

Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma

Nat Commun. 2019 Apr 11;10(1):1670. doi: 10.1038/s41467-019-09255-1.

Authors

Ting Yan^#^{1

2}, Heyang Cui^#^{1

2}, Yong Zhou^#^{1

2}, Bin Yang^#^{2

3}, Pengzhou Kong^#², Yingchun Zhang^#², Yiqian Liu², Bin Wang^{1

4}, Yikun Cheng⁵, Jiayi Li⁶, Shixing Guo², Enwei Xu^{2

7}, Huijuan Liu², Caixia Cheng^{2

8}, Ling Zhang², Ling Chen⁹, Xiaofei Zhuang³, Yu Qian², Jian Yang², Yanchun Ma², Hongyi Li², Fang Wang², Jing Liu^{2

10}, Xuefeng Liu¹, Dan Su¹¹, Yan Wang^{1

12}, Ruifang Sun¹³, Shiping Guo³, Yaoping Li¹⁴, Xiaolong Cheng², Zhihua Liu¹⁵, Qimin Zhan^{16

17}, Yongping Cui^{18

19}

Affiliations

¹ Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China.
² Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, 030001, Taiyuan, PR China.
³ Department of Tumor Surgery, Shanxi Cancer Hospital, 030013, Taiyuan, PR China.
⁴ College of Information and Computer, Taiyuan University of Technology, 030001, Taiyuan, PR China.
⁵ College of Letter & Science, University of California Berkeley, Berkeley, CA, 94704, USA.
⁶ Anglo-Chinese School (Independent), Singapore, 139650, Singapore.
⁷ Department of Pathology, Shanxi Cancer Hospital, 030013, Taiyuan, PR China.
⁸ Department of Pathology, the First Hospital, Shanxi Medical University, 030001, Taiyuan, PR China.
⁹ Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Gynecology Obstetrics Hospital, 300052, Tianjin, PR China.
¹⁰ Department of General Surgery, the First Hospital, Shanxi Medical University, 030001, Taiyuan, PR China.
¹¹ Department of Pathology, Zhejiang Cancer Hospital, 310022, Hangzhou, PR China.
¹² Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100191, Beijing, PR China.
¹³ Tumor Biobank, Shanxi Cancer Hospital, 030013, Taiyuan, PR China.
¹⁴ Department of Colorectal & Anal Surgery, Affiliated Provincial Hospital of Shanxi Medical University, 030001, Taiyuan, PR China.
¹⁵ State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, PR China.
¹⁶ Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China. [email protected].
¹⁷ Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, 100191, Beijing, PR China. [email protected].
¹⁸ Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China. [email protected].
¹⁹ Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, 030001, Taiyuan, PR China. [email protected].

^# Contributed equally.

Abstract

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Biomarkers, Tumor / antagonists & inhibitors
Biomarkers, Tumor / genetics
Carcinogenesis / genetics*
Cell Line, Tumor
China
Cohort Studies
DNA Copy Number Variations
Drug Resistance, Neoplasm / genetics
Esophageal Neoplasms / blood
Esophageal Neoplasms / genetics*
Esophageal Neoplasms / pathology
Esophageal Neoplasms / therapy
Esophageal Squamous Cell Carcinoma / blood
Esophageal Squamous Cell Carcinoma / genetics*
Esophageal Squamous Cell Carcinoma / pathology
Esophageal Squamous Cell Carcinoma / therapy
Esophagus / pathology
Esophagus / surgery
Exome Sequencing / methods
Female
Gene Amplification
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Genomics / methods
Humans
Male
Middle Aged
Molecular Targeted Therapy / methods
Precision Medicine / methods
Receptors, Antigen, T-Cell / antagonists & inhibitors
Receptors, Antigen, T-Cell / genetics
Transcriptome / genetics

Substances

Antineoplastic Agents
Biomarkers, Tumor
Receptors, Antigen, T-Cell