Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
Department of Nutrition Science, College of Health and Human Science, Purdue Center for Cancer Research, Purdue University, West Lafayette, IN, USA.
Carcinogenesis. 2019 Dec 31;40(12):1462-1468. doi: 10.1093/carcin/bgz159.
Mitochondrial DNA (mtDNA) is susceptible to oxidative stress and mutation. Few epidemiological studies have assessed the relationship between mtDNA copy number (mtDNAcn) and risk of colorectal cancer (CRC), with inconsistent findings. In this study, we examined the association between pre-diagnostic leukocyte mtDNAcn and CRC risk in a case-control study of 324 female cases and 658 matched controls nested within the Nurses' Health Study (NHS). Relative mtDNAcn in peripheral blood leukocytes was measured by quantitative polymerase chain reaction-based assay. Conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association of interest. Results showed lower log-mtDNAcn was significantly associated with increased risk of CRC, in a dose-dependent relationship (P for trend < 0.0001). Compared to the fourth quartile, multivariable-adjusted OR [95% confidence interval (CI)] was 1.10 (0.69, 1.76) for the third quartile, 1.40 (0.89, 2.19) for the second quartile and 2.19 (1.43, 3.35) for the first quartile. In analysis by anatomic subsite of CRC, we found a significant inverse association for proximal colon cancer [lowest versus highest quartile, multivariable-adjusted OR (95% CI) = 3.31 (1.70, 6.45), P for trend = 0.0003]. Additionally, stratified analysis according to the follow-up time since blood collection showed that the inverse association between mtDNAcn and CRC remained significant among individuals with ≥ 5 years' follow-up, and marginally significant among those with ≥ 10 years' follow-up since mtDNAcn testing, suggesting that mtDNAcn may serve as a long-term predictor for risk of CRC. In conclusion, pre-diagnostic leukocyte mtDNAcn was inversely associated with CRC risk. Further basic experimental studies are needed to explore the underlying biological mechanisms linking mtDNAcn to CRC carcinogenesis.
线粒体 DNA（mtDNA）易受氧化应激和突变的影响。少数流行病学研究评估了 mtDNA 拷贝数（mtDNAcn）与结直肠癌（CRC）风险之间的关系，但结果不一致。在这项研究中，我们在护士健康研究（NHS）中对 324 名女性病例和 658 名匹配对照进行了病例对照研究，检测了外周血白细胞中预诊断 mtDNAcn 与 CRC 风险之间的关系。通过基于定量聚合酶链反应的检测方法测量外周血白细胞中的相对 mtDNAcn。应用条件逻辑回归模型来估计感兴趣的关联的比值比（OR）和 95％置信区间（95％CI）。结果显示，log-mtDNAcn 水平越低，CRC 风险越高，呈剂量依赖性关系（趋势 P<0.0001）。与第四四分位相比，第三四分位的多变量调整 OR[95％置信区间（CI）]为 1.10（0.69，1.76），第二四分位为 1.40（0.89，2.19），第一四分位为 2.19（1.43，3.35）。按 CRC 的解剖部位进行分析，我们发现近端结肠癌存在显著的反比关系[最低与最高四分位，多变量调整 OR（95％CI）=3.31（1.70，6.45），趋势 P=0.0003]。此外，根据采血后随访时间的分层分析表明，mtDNAcn 与 CRC 之间的反比关系在随访时间≥5 年的个体中仍然显著，在 mtDNAcn 检测后随访时间≥10 年的个体中具有边缘显著意义，表明 mtDNAcn 可能是 CRC 风险的长期预测因子。总之，预诊断白细胞 mtDNAcn 与 CRC 风险呈负相关。需要进一步的基础实验研究来探索将 mtDNAcn 与 CRC 癌变联系起来的潜在生物学机制。
