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食管鳞状细胞癌（ESCC）治疗选择有限，一些靶向药物已用于ESCC，例如吉非替尼（EGFR抑制剂），Dovitinib（FGFR1抑制剂）和PD-L1阻断剂。然而，只有一小部分患者从这些靶向治疗中获得长期益处，这引发了癌症细胞的肿瘤内异质性（ITH）或肿瘤免疫微环境如肿瘤浸润淋巴细胞和衍生T细胞受体的问题。本篇文献揭示了来自同一ESCC患者不同区域的样本中可药物靶标或生物标记物的高水平异质性，突出了多区域测序对于精确治疗的必要性。
Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma
图片来源：文献原文
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 focalhigh-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.
多区域测序揭示了食管鳞状细胞癌的新型可操作靶点和空间异质性
由于缺乏有效的分子标记，食管鳞状细胞癌（esophagealsquamous cell carcinoma，ESCC）在中国的癌症相关死亡率中排名第四。我们收集了39名ESCC患者的样本，对肿瘤的不同区域，，正常组织和血液进行了全外显子组和T细胞受体（TCR）全测序。数据显示在有12.8％的患者发生ERBB4突变，并且功能学研究证实其致癌作用。18％患者携带有早期BRCA1 / 2变异，与高水平的标签3（同源重组损伤修复相关）相关，这在独立的大型队列（n = 508）中得到验证。此外，BRCA1 / 2的敲除显示对ESCC细胞中顺铂的敏感性增加。5％的患者具有局灶性高水平CD274的扩增，导致PD-L1的大量表达，并且可能对免疫监控点更敏感。最后，我们发现了基因组和TCR谱系与肿瘤内异质性的密切关系。总的来说，我们揭示了ESCC患者，高水平的肿瘤内异质性，确定了几个潜在的靶标，可能对ESCC的诊疗提供新见解。
文献来源
doi：10.1038/ s41467-019-09255-1
备注：浦美医学每周推出一个专题的“文献速递”汇编，如需详细了解内容或全文请联系我们（浦美小编：微信号pumeixiaobian）。文献内容均由浦美医学编译自原文，疏漏之处敬请读者指正。
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