Qu Falin, Chen Yibing, Wang Xin, He Xianli, Ren Tingting, Huang Qichao, Zhang Jing, Liu Xiaonan, Guo Xu, Gu Jian, Xing Jinliang
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Department of General Surgery, Tangdu Hospital and.
State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine.
Carcinogenesis. 2015 May;36(5):543-52. doi: 10.1093/carcin/bgv042. Epub 2015 Mar 30.
Compelling evidence has indicated a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risks of several malignancies in a cancer-specific manner. However, to date, whether leukocyte mtDNA content can predict clinical outcome of cancer patients has never been investigated. In the present study, we measured leukocyte mtDNA content using real-time PCR-based method in a total of 598 colorectal cancer (CRC) patients and explored its prognostic values. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in CRC patients. We found that patients with high mtDNA content showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with low mtDNA content in all patient sets. Furthermore, mtDNA content and tumor node metastasis (TNM) stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte mtDNA content significantly improved the prognosis prediction efficacy for CRC. Importantly, patients with high mtDNA content showed OS and RFS benefits from adjuvant chemotherapy. In addition, we found that patients with high mtDNA content had a higher frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells, higher plasma interleukin-2 and transforming growth factor-β1 and lower tumor necrosis factor-α concentration than those with low mtDNA content, suggesting a stronger immunosuppressive phenotype. In conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with immunosuppression in CRC patients. Additionally, leukocyte mtDNA content might serve as a potential biomarker to select CRC patients who will benefit from adjuvant chemotherapy.
有力证据表明，白细胞线粒体DNA（mtDNA）含量与几种恶性肿瘤的发病风险之间存在癌症特异性的显著关联。然而，迄今为止，白细胞mtDNA含量能否预测癌症患者的临床结局尚未得到研究。在本研究中，我们采用基于实时PCR的方法测量了598例结直肠癌（CRC）患者的白细胞mtDNA含量，并探讨了其预后价值。为了探究潜在机制，我们检测了CRC患者外周血单个核细胞的免疫表型和几种细胞因子的血浆浓度。我们发现，在所有患者组中，mtDNA含量高的患者总生存期（OS）和无复发生存期（RFS）明显比mtDNA含量低的患者差。此外，mtDNA含量和肿瘤淋巴结转移（TNM）分期在预后预测中表现出显著的联合效应。TNM分期和白细胞mtDNA含量的整合显著提高了CRC的预后预测效能。重要的是，mtDNA含量高的患者从辅助化疗中获得了OS和RFS益处。此外，我们发现，mtDNA含量高的患者比mtDNA含量低的患者具有更高频率的CD4(+)CD25(+)FOXP3(+)调节性T细胞、更高的血浆白细胞介素-2和转化生长因子-β1以及更低的肿瘤坏死因子-α浓度，提示更强的免疫抑制表型。总之，我们的研究首次表明，白细胞mtDNA含量是补充TNM分期的独立预后标志物，且与CRC患者的免疫抑制相关。此外，白细胞mtDNA含量可能作为一种潜在的生物标志物，用于选择将从辅助化疗中获益的CRC患者。
