新辅助放化疗驱动的食管鳞状细胞癌基因组和免疫基因组的进化。
Evolution of genome and immunogenome in esophageal squamous cell carcinomas driven by neoadjuvant chemoradiotherapy.
发表日期：2024 Jul 31
作者：
Zelin Weng, Zihang Mai, Jianye Yuan, Qianwen Liu, Fangqi Deng, Hong Yang, Yihong Ling, Xiuying Xie, Xiaodan Lin, Ting Lin, Jiyang Chen, Xiaoli Wei, Kongjia Luo, Jianhua Fu, Jing Wen
来源：
INTERNATIONAL JOURNAL OF CANCER
摘要：
新辅助放化疗 (NCRT) 随后进行手术是局部晚期食管鳞状细胞癌 (ESCC) 的标准治疗方法。然而，NCRT 驱动的 ESCC 基因组和免疫基因组的进化仍未完全阐明。我们对 NCRT 前后收集的 51 个 ESCC 肿瘤进行了全外显子组测序，其中 36 个进行了转录组测序。克隆分析确定了 13 名 ESCC 患者的克隆消失，其中所有 NCRT 前的克隆在 NCRT 后消失，以及 9 名患者的克隆持续，其中克隆在 NCRT 后持续存在。与克隆消失的患者相比，克隆持续存在的患者在 NCRT 前表现出更高的基因组瘤内异质性和更差的预后。与克隆灭绝的患者相比，克隆持续的患者在治疗前标本中表现出高比例的亚克隆新抗原。转录组分析显示，NCRT 后免疫浸润增加，免疫相关通路上调，尤其是在克隆灭绝患者中。克隆灭绝患者中 T 细胞受体-新抗原相互作用的数量高于克隆持续患者。 T细胞库均匀度的降低与NCRT后克隆新抗原数量的减少呈正相关，尤其是在克隆灭绝的患者中。总之，我们确定了 ESCC 中由 NCRT 驱动的两种与预后相关的克隆动态模式。这项研究扩展了我们对 NCRT 驱动的 ESCC 基因组和免疫基因组进化的了解。© 2024 UICC。
Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinomas (ESCCs). However, the evolution of genome and immunogenome in ESCCs driven by NCRT remains incompletely elucidated. We performed whole-exome sequencing of 51 ESCC tumors collected before and after NCRT, 36 of which were subjected to transcriptome sequencing. Clonal analysis identified clonal extinction in 13 ESCC patients wherein all pre-NCRT clones disappeared after NCRT, and clonal persistence in 9 patients wherein clones endured following NCRT. The clone-persistent patients showed higher pre-NCRT genomic intratumoral heterogeneity and worse prognosis than the clone-extinct ones. In contrast to the clone-extinct patients, the clone-persistent patients demonstrated a high proportion of subclonal neoantigens within pre-treatment specimens. Transcriptome analysis revealed increased immune infiltrations and up-regulated immune-related pathways after NCRT, especially in the clone-extinct patients. The number of T cell receptor-neoantigen interactions was higher in the clone-extinct patients than in the clone-persistent ones. The decrease in T cell repertoire evenness positively correlated to the decreased number of clonal neoantigens after NCRT, especially in the clone-extinct patients. In conclusion, we identified two prognosis-related clonal dynamic modes driven by NCRT in ESCCs. This study extended our knowledge of the ESCC genome and immunogenome evolutions driven by NCRT.© 2024 UICC.