Mitochondrial DNA Haplogroup N9a Negatively Correlates with Incidence of Hepatocellular Carcinoma in Northern China
Mitochondrial DNA Haplogroup N9a Negatively Correlates with Incidence of Hepatocellular Carcinoma in Northern China
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线粒体DNA单倍群N9a与中国北方肝细胞癌的发病率呈负相关
DOI：
10.1016/j.omtn.2019.09.001
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发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Shen, Lijun
中科院分区：
文献类型：
--
作者：
Hua, Shixuan;Li, Meinan;Shen, Lijun
线粒体DNA（mtDNA）单倍型群与各种类型的癌症相关;然而，mtDNA单倍型群影响原发性肝细胞癌（HCC）的分子机制尚不清楚。在这项研究中，我们进行了一项病例对照研究，388例肝癌患者和511名无症状对照者在北方中国。我们发现mtDNA单倍型群N9 a及其诊断性SNP m.16257C > A与中国北方地区肝癌发病率呈负相关（比值比[OR] 0.290，95%置信区间[CI] 0.123-0.685，p = 0.005），尤其是在感染B/C型肝炎病毒（HBV/HCV）的患者中（单倍群N9 a：OR 0.213，95%CI 0.077-0.590，p = 0.003; m.16257C > A：OR 0.262，95%CI 0.107-0.643，p = 0.003）。然而，mtDNA单倍型组N9 a与HCC的临床特征，包括血清甲胎蛋白（AFP）水平和肿瘤大小无关。此外，具有N9 a单倍型群（N9 a10 a和N9 a1）的细胞质杂种（胞质杂种）细胞具有与具有非N9 a（B5、D4和D5）单倍型群的细胞不同的转录组谱。基因集富集分析（GSEA）表明，N9 a和非N9 a单倍型组之间的代谢活性差异显着。此外，与非N9 a细胞相比，具有单倍群N9 a的细胞与细胞分裂和多种肝癌途径呈负相关。虽然N9 a对上述GSEA通路的影响尚不清楚，但我们的数据表明mtDNA单倍型群N9 a与中国北方肝癌的发病率和进展呈负相关。
Mitochondrial DNA (mtDNA) haplogroups are associated with various types of cancer; however, the molecular mechanisms by which mtDNA haplogroups affect primary hepatocellular carcinoma (HCC) are not known. In this study, we carried out a case-control study on 388 HCC patients and 511 geographically matched asymptomatic control subjects in northern China. We found that mtDNA haplogroup N9a and its diagnostic SNP, m.16257C > A, negatively correlated with the incidence of HCC in northern China (odds ratio [OR] 0.290, 95% confidence interval [CI] 0.123-0.685, p = 0.005), particularly in patients with infection of hepatitis B/C virus (HBV/HCV) (for haplogroup N9a: OR 0.213, 95% CI 0.077-0.590, p = 0.003; for m.16257C > A: OR 0.262, 95% CI 0.107-0.643, p = 0.003). However, mtDNA haplogroup N9a is not associated with clinical characteristics of HCC including serum alpha-fetoprotein (AFP) level and tumor size. In addition, cytoplasmic hybrid (cybrid) cells with N9a haplogroup (N9a10a and N9a1) had transcriptome profiles distinct from those with non-N9a (B5, D4, and D5) haplogroups. Gene set enrichment analysis (GSEA) showed that metabolic activity varied significantly between N9a and non-N9a haplogroups. Moreover, cells with haplogroup N9a negatively correlated with cell division and multiple liver cancer pathways compared with non-N9a cells. Although it is still unclear how N9a affects the aforementioned GSEA pathways, our data suggest that mtDNA haplogroup N9a is negatively correlated with the incidence and progression of HCC in northern China.