The Mitochondrial DNA Northeast Asia CZD Haplogroup Is Associated with Good Disease-Free Survival among Male Oral Squamous Cell Carcinoma Patients

Reprogramming of energy metabolism in cancer cells has been directly/indirectly linked to mitochondria and mitochondrial functional defects and these changes seem to contribute to the development and progression of cancer. Studies have indicated that mitochondrial DNA haplogroups are associated with risk in relation to various diseases including cancer. However, few studies have examined the effect of haplogroups on cancer prognosis outcome. In order to explore the role of haplogroups on oral squamous cell carcinoma (OSCC) prognosis, the mitochondrial genomes of 300 male OSCC patients were comprehensively analyzed by direct sequencing. They were then haplotyped and grouped into four major geographic haplogroups, namely the East Asia AN, Southeast Asia RBF, East Asia MGE and Northeast Asia CZD groups. The Kaplan-Meier plot analysis indicated that individuals who were members of the CZD haplogroup showed a significant association with better disease-free survival (DFS) than the other three haplogroups and this phenomenon still existed after adjusting for tumor stage, differentiation and age at diagnosis (hazard ratio = 0.55; 95% CI = 0.36–0.84). In addition, an interaction between membership of the RBF haplogroup and radiotherapy/chemo-radiotherapy in DFS was also identified. The results strongly support the hypothesis that an individual’s haplogroup, by defining their genomic background, plays an important role in tumor behavior and mitochondrially-targeted anticancer drugs are promising future therapeutic approaches.

癌细胞能量代谢重编程已被直接或间接证实与线粒体及线粒体功能缺陷相关，此类代谢改变似乎可促进癌症的发生与进展。已有研究表明，线粒体DNA单倍群（mitochondrial DNA haplogroups）与包括癌症在内的多种疾病的发病风险相关。但目前鲜有研究探讨单倍群对癌症预后结局的影响。为探究单倍群在口腔鳞状细胞癌（oral squamous cell carcinoma, OSCC）预后中的作用，本研究通过直接测序技术对300例男性口腔鳞状细胞癌患者的线粒体基因组进行了全面分析。随后对样本进行单倍型分型，并将其划分为四大地理源性单倍群，即东亚AN、东南亚RBF、东亚MGE以及东北亚CZD组。Kaplan-Meier生存曲线分析结果显示，携带CZD单倍群的患者无病生存期（disease-free survival, DFS）显著优于其余三个单倍群组；在校正肿瘤分期、分化程度及诊断年龄后，该差异仍具有统计学意义（风险比=0.55；95%置信区间=0.36–0.84）。此外，本研究还发现RBF单倍群携带状态与放化疗/同步放化疗在无病生存期上存在交互效应。本研究结果有力支持了如下假说：个体所携带的单倍群通过界定其基因组背景，在肿瘤生物学行为中发挥重要作用；而靶向线粒体的抗肿瘤药物有望成为未来极具前景的治疗策略。