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- Title
Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma.
- Authors
Yan, Ting; Cui, Heyang; Zhou, Yong; Yang, Bin; Kong, Pengzhou; Zhang, Yingchun; Liu, Yiqian; Wang, Bin; Cheng, Yikun; Li, Jiayi; Guo, Shixing; Xu, Enwei; Liu, Huijuan; Cheng, Caixia; Zhang, Ling; Chen, Ling; Zhuang, Xiaofei; Qian, Yu; Yang, Jian; Ma, Yanchun
- 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. Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China. Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274; together with high levels of genomic and T-cell receptor heterogeneity.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-09255-1