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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 10 Issue 1 Pg. 1670 (04 11 2019) ISSN: 2041-1723 [Electronic] England
• PMID: 30975989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor (antagonists & inhibitors, genetics)
• Carcinogenesis (genetics)
• Cell Line, Tumor
• China
• Cohort Studies
• DNA Copy Number Variations
• Drug Resistance, Neoplasm (genetics)
• Esophageal Neoplasms (blood, genetics, pathology, therapy)
• Esophageal Squamous Cell Carcinoma (blood, genetics, pathology, therapy)
• Esophagus (pathology, surgery)
• 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, genetics)
• Transcriptome (genetics)
• Exome Sequencing (methods)