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 () and Yongping Cui ()
Additional contact information
Ting Yan: Peking University Shenzhen Hospital
Heyang Cui: Peking University Shenzhen Hospital
Yong Zhou: Peking University Shenzhen Hospital
Bin Yang: Shanxi Medical University
Pengzhou Kong: Shanxi Medical University
Yingchun Zhang: Shanxi Medical University
Yiqian Liu: Shanxi Medical University
Bin Wang: Peking University Shenzhen Hospital
Yikun Cheng: University of California Berkeley
Jiayi Li: Anglo-Chinese School (Independent)
Shixing Guo: Shanxi Medical University
Enwei Xu: Shanxi Medical University
Huijuan Liu: Shanxi Medical University
Caixia Cheng: Shanxi Medical University
Ling Zhang: Shanxi Medical University
Ling Chen: Nankai University Gynecology Obstetrics Hospital
Xiaofei Zhuang: Shanxi Cancer Hospital
Yu Qian: Shanxi Medical University
Jian Yang: Shanxi Medical University
Yanchun Ma: Shanxi Medical University
Hongyi Li: Shanxi Medical University
Fang Wang: Shanxi Medical University
Jing Liu: Shanxi Medical University
Xuefeng Liu: Peking University Shenzhen Hospital
Dan Su: Zhejiang Cancer Hospital
Yan Wang: Peking University Shenzhen Hospital
Ruifang Sun: Shanxi Cancer Hospital
Shiping Guo: Shanxi Cancer Hospital
Yaoping Li: Affiliated Provincial Hospital of Shanxi Medical University
Xiaolong Cheng: Shanxi Medical University
Zhihua Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Qimin Zhan: Peking University Shenzhen Hospital
Yongping Cui: Peking University Shenzhen Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09255-1

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