Liver is the most common site where metastatic lesions of colorectal cancer (CRC) arise. Although researches have shown mutations in driver genes, copy number variations (CNV) and alterations in relevant signaling pathways promoted the tumor evolution and immune escape during colorectal liver metastasis (CLM), the underlying mechanism remains largely elusive. Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during CLM. Shared somatic mutations between primary and metastatic tissues with a commonly observed subclonal-clonal (S-C) changing pattern indicated a common clonal origin between two lesions. The recurrent mutations with S-C changing pattern included those in KRAS, SYNE1, CACNA1H, PCLO, FBXL2, and DNAH11. The main CNV events underwent clonal-clonal evolution (20q amplification (amp), 17p deletion (del), 18q del and 8p del), subclonal-clonal evolution (8q amp, 13q amp, 8p del) and metastasis-specific evolution (8q amp) during the process of CLM. In addition, we revealed a potential mechanism of tumor cell immune escape by analyzing human leukocytes antigens (HLA) related clonal neoantigens and immune cell components in CLM. Our study proposed a novel liver metastasis-related evolutionary process in colorectal cancer and emphasized the theory of neo-immune escape in colorectal liver metastasis.

肝脏是结直肠癌 (CRC) 发生转移性病变的最常见部位。尽管研究表明驱动基因的突变、拷贝数变异 (CNV) 和相关信号通路的改变促进了结直肠肝转移 (CLM) 过程中的肿瘤进化和免疫逃逸，但其潜在机制仍然难以捉摸。从 16 名诊断为结直肠癌的患者中收集肿瘤和匹配的转移组织，并进行全外显子组测序 (WES) 和 RNA 测序 (RNA-seq)，用于研究 CLM 期间的结直肠癌克隆进化和免疫逃逸。原发性和转移性组织之间共享的体细胞突变具有常见的亚克隆-克隆 (SC) 变化模式，表明两个病变之间存在共同的克隆起源。KRAS、SYNE1、CACNA1H、PCLO、FBXL2 和 DNAH11。主要的 CNV 事件经历了克隆-克隆进化（20q 扩增（amp）、17p 缺失（del）、18q del 和 8p del）、亚克隆-克隆进化（8q amp、13q amp、8p del）和转移特异性进化（8q amp) 在 CLM 过程中。此外，我们通过分析 CLM 中与人类白细胞抗原 (HLA) 相关的克隆新抗原和免疫细胞成分，揭示了肿瘤细胞免疫逃逸的潜在机制。我们的研究提出了一种新的结直肠癌肝转移相关进化过程，并强调了结直肠癌肝转移中新免疫逃逸的理论。