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

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

Yan T1,2, Cui H1,2, Zhou Y1,2, Yang B2,3, Kong P2, Zhang Y2, Liu Y2, Wang B1,4, Cheng Y5, Li J6, Guo S2, Xu E2,7, Liu H2, Cheng C2,8, Zhang L2, Chen L9, Zhuang X3, Qian Y2, Yang J2, Ma Y2, Li H2, Wang F2, Liu J2,10, Liu X1, Su D11, Wang Y1,12, Sun R13, Guo S3, Li Y14, Cheng X2, Liu Z15, Zhan Q16,17, Cui Y18,19.

Author information

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. zhanqimin@bjmu.edu.cn.
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. zhanqimin@bjmu.edu.cn.
18
Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China. cuiyp@sphmc.org.
19
Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, 030001, Taiyuan, PR China. cuiyp@sphmc.org.

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.

PMID:
30975989
PMCID:
PMC6459928
DOI:
10.1038/s41467-019-09255-1
[Indexed for MEDLINE]
Free PMC Article

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