具有错配修复缺陷/微卫星不稳定性高（dMMR/MSI-H）状态的结直肠癌（CRC）患者通常被认为对辅助化疗（ACT）无反应。线粒体转录因子 A (TFAM) 是线粒体 DNA 拷贝数 (mtDNA-CN) 表达所必需的。鉴于之前的研究结果表明 TFAM 的频繁截短突变会影响 MSI CRC 细胞的化疗耐药性，本研究旨在探讨 mtDNA-CN 作为 dMMR CRC 患者 ACT 疗效预测生物标志物的潜力。使用定量实时聚合酶链反应 (qRT-PCR) 对 308 名患有 dMMR 的 CRC 患者（其中 180 名 II 期患者和 128 名 III 期患者）进行了 CN 评估。收集临床病理学和治疗数据。该研究探讨了 mtDNA-CN 水平与预后之间的关联，以及 ACT 获益对 dMMR CRC 患者的影响。主要根据肿瘤分期和mtDNA-CN水平进行亚组分析。采用Kaplan-Meier和Cox回归模型评估mtDNA-CN对无病生存（DFS）和总生存（OS）的影响。在肿瘤组织中观察到mtDNA-CN表达大幅减少，并且mtDNA-CN表达升高。 CN 水平与 dMMR CRC 患者的 DFS（73.4% vs 85.7%；P = 0.0055）和 OS（82.5% vs 90.3%；P = 0.0366）改善相关。 Cox 回归分析确定高 mtDNA-CN 是 DFS（风险比 [HR] 0.547；95% 置信区间 [CI] 0.321-0.934；P = 0.0270）和 OS（HR 0.520；95% CI 0.272-0.998）的独立保护因素; P = 0.0492)。值得注意的是，对于 mtDNA-CN 升高的 dMMR CRC 患者，ACT 显着改善 DFS（74.6% vs 93.4%；P = 0.0015）和 OS（81.0% vs 96.7%；P = 0.0017），包括 II 期或 III 期疾病的患者。 mtDNA-CN 水平与具有 dMMR 的 II 期或 III 期 CRC 患者的预后相关。 mtDNA-CN 升高成为一个强有力的预后因素，表明患有 dMMR 的 II 期和 III 期 CRC 患者的 ACT 结局有所改善。这些发现表明 mtDNA-CN 作为指导该人群个性化 ACT 治疗的生物标志物的潜在效用。© 2024。作者。

Colorectal cancer (CRC) patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) status are conventionally perceived as unresponsive to adjuvant chemotherapy (ACT). The mitochondrial transcription factor A (TFAM) is required for mitochondrial DNA copy number (mtDNA-CN) expression. In light of previous findings indicating that the frequent truncating-mutation of TFAM affects the chemotherapy resistance of MSI CRC cells, this study aimed to explore the potential of mtDNA-CN as a predictive biomarker for ACT efficacy in dMMR CRC patients.Levels of MtDNA-CN were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) in a cohort of 308 CRC patients with dMMR comprising 180 stage II and 128 stage III patients. Clinicopathologic and therapeutic data were collected. The study examined the association between mtDNA-CN levels and prognosis, as well as the impact of ACT benefit on dMMR CRC patients. Subgroup analyses were performed based mainly on tumor stage and mtDNA-CN level. Kaplan-Meier and Cox regression models were used to evaluate the effect of mtDNA-CN on disease-free survival (DFS) and overall survival (OS).A substantial reduction in mtDNA-CN expression was observed in tumor tissue, and higher mtDNA-CN levels were correlated with improved DFS (73.4% vs 85.7%; P = 0.0055) and OS (82.5% vs 90.3%; P = 0.0366) in dMMR CRC patients. Cox regression analysis identified high mtDNA-CN as an independent protective factor for DFS (hazard ratio [HR] 0.547; 95% confidence interval [CI] 0.321-0.934; P = 0.0270) and OS (HR 0.520; 95% CI 0.272-0.998; P = 0.0492). Notably, for dMMR CRC patients with elevated mtDNA-CN, ACT significantly improved DFS (74.6% vs 93.4%; P = 0.0015) and OS (81.0% vs 96.7%; P = 0.0017), including those with stage II or III disease.The mtDNA-CN levels exhibited a correlation with the prognosis of stage II or III CRC patients with dMMR. Elevated mtDNA-CN emerges as a robust prognostic factor, indicating improved ACT outcomes for stages II and III CRC patients with dMMR. These findings suggest the potential utility of mtDNA-CN as a biomarker for guiding personalized ACT treatment in this population.© 2024. The Author(s).