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

Author

Listed:
  • Ting Yan

    (Peking University Shenzhen Hospital
    Shanxi Medical University)

  • Heyang Cui

    (Peking University Shenzhen Hospital
    Shanxi Medical University)

  • Yong Zhou

    (Peking University Shenzhen Hospital
    Shanxi Medical University)

  • Bin Yang

    (Shanxi Medical University
    Shanxi Cancer Hospital)

  • Pengzhou Kong

    (Shanxi Medical University)

  • Yingchun Zhang

    (Shanxi Medical University)

  • Yiqian Liu

    (Shanxi Medical University)

  • Bin Wang

    (Peking University Shenzhen Hospital
    Taiyuan University of Technology)

  • Yikun Cheng

    (University of California Berkeley)

  • Jiayi Li

    (Anglo-Chinese School (Independent))

  • Shixing Guo

    (Shanxi Medical University)

  • Enwei Xu

    (Shanxi Medical University
    Shanxi Cancer Hospital)

  • Huijuan Liu

    (Shanxi Medical University)

  • Caixia Cheng

    (Shanxi Medical University
    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
    Shanxi Medical University)

  • Xuefeng Liu

    (Peking University Shenzhen Hospital)

  • Dan Su

    (Zhejiang Cancer Hospital)

  • Yan Wang

    (Peking University Shenzhen Hospital
    Peking University Cancer Hospital & Institute)

  • 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
    Peking University Cancer Hospital & Institute)

  • Yongping Cui

    (Peking University Shenzhen Hospital
    Shanxi Medical University)

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.

Suggested Citation

  • 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, 2019. "Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09255-1
    DOI: 10.1038/s41467-019-09255-1
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    Cited by:

    1. Guozhong Jiang & Zhizhong Wang & Zhenguo Cheng & Weiwei Wang & Shuangshuang Lu & Zifang Zhang & Chinedu A. Anene & Faraz Khan & Yue Chen & Emma Bailey & Huisha Xu & Yunshu Dong & Peinan Chen & Zhongxi, 2024. "The integrated molecular and histological analysis defines subtypes of esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. De-Chen Lin, 2023. "Large-scale genomic analyses reveal alterations and mechanisms underlying clonal evolution and immune evasion in esophageal cancer," Nature Communications, Nature, vol. 14(1), pages 1-3, December.
    3. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Sijia Cui & Nicholas McGranahan & Jing Gao & Peng Chen & Wei Jiang & Lingrong Yang & Li Ma & Junfang Liao & Tian Xie & Congying Xie & Tariq Enver & Shixiu Wu, 2023. "Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Heyang Cui & Yong Zhou & Fang Wang & Caixia Cheng & Weimin Zhang & Ruifang Sun & Ling Zhang & Yanghui Bi & Min Guo & Yan Zhou & Xinhui Wang & Jiaxin Ren & Ruibing Bai & Ning Ding & Chen Cheng & Longlo, 2022. "Characterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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