染色体不稳定性在实体瘤中的分子机制及临床意义——以肺癌为重点

Molecular Mechanisms and Clinical Significance of Chromosomal Instability in Solid Tumors: A Focus on Lung Cancer

摘要: 染色体不稳定性(Chromosomal Instability, CIN)是指细胞有丝分裂过程中染色体错误分离频率异常升高，导致染色体数目和结构持续改变的动态过程，是癌症的标志性特征之一。CIN主要表现为数目异常(非整倍体、全基因组加倍)和结构异常(缺失、扩增、易位、染色体碎裂等)，其发生机制涉及纺锤体组装检查点缺陷、姐妹染色单体粘连异常、DNA复制应激、端粒功能障碍及DNA修复缺陷等多个层面。CIN的检测方法涵盖传统细胞遗传学、高通量测序(WGS、WES、SNP芯片)及单细胞与液体活检技术。在实体瘤中，CIN通过驱动肿瘤异质性、促进转移、重塑免疫微环境及调控治疗应答发挥核心作用。CIN通过激活cGAS-STING通路、诱导上皮–间质转化及免疫抑制，促进肿瘤侵袭转移；其水平与免疫细胞浸润及免疫治疗疗效密切相关。CIN70基因标签等高通量指标在多种癌症中具有预后评估价值。在肺癌中，约60%~80%的非小细胞肺癌存在CIN，并与TP53、FAT1、STK11等驱动基因突变密切相关。吸烟通过抑制FANCD2表达诱导CIN发生。CIN通过慢性激活cGAS-STING通路导致EGFR突变型肺癌对EGFR-TKI耐药，而STK11突变型肺癌则呈现高CIN及免疫治疗抵抗。基于CIN脆弱性的靶向策略(如cGAS-STING通路、DNA修复通路)展现出临床应用前景。未来，CIN研究需解决动态监测标准化及临床转化问题，有望成为指导肺癌个体化治疗的新型生物标志物。

Abstract: Chromosomal instability (CIN) is a hallmark of cancer characterized by an elevated rate of chromosome mis-segregation during mitosis, leading to persistent numerical and structural chromosomal alterations. CIN manifests as aneuploidy, whole-genome doubling, deletions, amplifications, translocations, and chromothripsis, arising from spindle checkpoint defects, cohesion abnormalities, replication stress, telomere dysfunction, and DNA repair deficiencies. Detection methods include cytogenetics, high-throughput sequencing (WGS, WES, SNP arrays), and liquid biopsy. In solid tumors, CIN drives heterogeneity, metastasis, immune remodeling, and treatment response. CIN promotes invasion and metastasis via cGAS-STING activation, epithelial-mesenchymal transition, and immunosuppression. CIN levels correlate with immune infiltration and immunotherapy efficacy, with metrics like the CIN70 signature showing prognostic value across cancers. In lung cancer, CIN occurs in 60%~80% of non-small cell lung cancer cases and associates with TP53, FAT1, and STK11 mutations. Smoking induces CIN via FANCD2 suppression. CIN drives EGFR-TKI resistance in EGFR-mutant lung cancer through chronic cGAS-STING activation, while STK11-mutant tumors exhibit high CIN and immunotherapy resistance. Targeting CIN vulnerabilities (e.g., cGAS-STING, DNA repair pathways) shows clinical promise. Future efforts should focus on standardizing dynamic CIN monitoring and facilitating clinical translation, positioning CIN as a novel biomarker for personalized lung cancer therapy.