PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：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。根据先前的研究结果表明，TFAM的频繁截断突变会影响MSICRC细胞的化疗抗性，本研究旨在探讨mtDNA-CN作为dMMRCRC患者ACT疗效预测生物标志物的潜力.
方法：使用定量实时聚合酶链反应（qRT-PCR）评估308例dMMRCRC患者的MtDNA-CN水平，包括180例II期和128例III期患者。收集临床病理和治疗数据。该研究检查了mtDNA-CN水平与预后之间的关系，以及ACT获益对dMMRCRC患者的影响。亚组分析主要基于肿瘤分期和mtDNA-CN水平进行。采用Kaplan-Meier和Cox回归模型评价mtDNA-CN对无病生存期(DFS)和总生存期(OS)的影响。
结果：在肿瘤组织中观察到mtDNA-CN表达显著减少，在dMMRCRC患者中，较高的mtDNA-CN水平与改善的DFS（73.4％vs85.7％；P=0.0055）和OS（82.5％vs90.3％；P=0.0366）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（HR0.520;95％CI0.272-0.998;P=0.0492）的独立保护因素。值得注意的是,对于mtDNA-CN升高的dMMRCRC患者，ACT显著提高了DFS(74.6%vs93.4%;P=0.0015)和OS(81.0%vs96.7%;P=0.0017),包括患有II期或III期疾病的患者。
结论：mtDNA-CN水平与患有dMMR的II期或III期CRC患者的预后相关。mtDNA-CN升高是一个强有力的预后因素，提示有dMMR的II期和III期CRC患者的ACT结局改善。这些发现表明mtDNA-CN作为指导该人群中个性化ACT治疗的生物标志物的潜在用途。
方法：使用定量实时聚合酶链反应（qRT-PCR）评估308例dMMRCRC患者的MtDNA-CN水平，包括180例II期和128例III期患者。收集临床病理和治疗数据。该研究检查了mtDNA-CN水平与预后之间的关系，以及ACT获益对dMMRCRC患者的影响。亚组分析主要基于肿瘤分期和mtDNA-CN水平进行。采用Kaplan-Meier和Cox回归模型评价mtDNA-CN对无病生存期(DFS)和总生存期(OS)的影响。
结果：在肿瘤组织中观察到mtDNA-CN表达显著减少，在dMMRCRC患者中，较高的mtDNA-CN水平与改善的DFS（73.4％vs85.7％；P=0.0055）和OS（82.5％vs90.3％；P=0.0366）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（HR0.520;95％CI0.272-0.998;P=0.0492）的独立保护因素。值得注意的是,对于mtDNA-CN升高的dMMRCRC患者，ACT显著提高了DFS(74.6%vs93.4%;P=0.0015)和OS(81.0%vs96.7%;P=0.0017),包括患有II期或III期疾病的患者。
结论：mtDNA-CN水平与患有dMMR的II期或III期CRC患者的预后相关。mtDNA-CN升高是一个强有力的预后因素，提示有dMMR的II期和III期CRC患者的ACT结局改善。这些发现表明mtDNA-CN作为指导该人群中个性化ACT治疗的生物标志物的潜在用途。
