PO.PS01.07 · 人群科学
线粒体DNA断裂与拷贝数及从不吸烟女性的肺癌风险
Mitochondrial DNA breaks and copy number and the risk of lung cancer in never-smoking women
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言 肺癌是全球癌症相关死亡的首要原因,约25%的病例发生于从不吸烟者,尤其是东亚女性。线粒体是细胞能量产生和氧化应激反应的关键调节者,而线粒体DNA(mtDNA)尤其易受环境暴露的损伤。虽然既往关于mtDNA拷贝数(mtDNAcn)与肺癌风险的研究结果不一致,但含断裂的mtDNA比例(mtDNAfb)近来作为氧化应激和线粒体完整性的潜在标志物而出现。我们在前瞻性上海女性健康研究(SWHS)中考察了从不吸烟女性诊断前mtDNAfb、mtDNAcn与肺癌风险之间的关联。方法 这项巢式病例对照研究纳入了789例肺癌事件病例和789例对照,他们按出生年份和采血日期进行个体匹配,来自SWHS——一个1996年至2000年间纳入74,942名女性的前瞻性队列。从白细胞或颊细胞中提取DNA,使用高通量qPCR分析比较TaqI处理(消化)和未处理样本的扩增信号来定量mtDNAfb。相对mtDNAcn由qPCR测量值归一化至参考基因得出。使用条件逻辑回归估计mtDNAfb和mtDNAcn与肺癌风险关联的比值比(OR)和95%置信区间(CI),校正了年龄、身体质量指数和分析板。敏感性分析进一步控制了教育程度、环境烟草烟雾暴露、肺癌家族史,以及mtDNAfb和mtDNAcn的相互校正。在乘法尺度上检验了mtDNAfb和mtDNAcn之间的交互作用。结果 我们观察到较高的mtDNAfb与较低的肺癌风险相关,mtDNAfb最高三分位数的参与者与最低三分位数者相比,其发病几率低34%(p趋势=0.026)。mtDNAcn未观察到独立关联;然而,识别出mtDNAfb和mtDNAcn之间的乘法交互作用(p交互=8.3×10⁻⁶),其中mtDNAfb与肺癌之间的关联在低mtDNAcn的参与者中(OR=0.47,95%CI:0.29-0.78)比高mtDNAcn者中(OR=1.02,95%CI:0.58-1.79)更为明显。结论 较低的mtDNAfb与从不吸烟女性肺癌风险增加相关,尤其是在低mtDNAcn的女性中,提示线粒体生物发生和功能可能存在病理性减退,进而导致固有免疫激活减弱。这些发现为线粒体功能障碍作为从不吸烟者肺癌潜在机制提供了新见解,值得在未来研究中进行复制和机制探究。
查看英文原文 English abstract
Introduction Lung cancer is the leading cause of cancer-related mortality worldwide, with approximately 25% of cases occurring in never-smokers, particularly East Asian women. Mitochondria are critical regulators of cellular energy production and oxidative stress responses, and mitochondrial DNA (mtDNA) is especially susceptible to damage from environmental exposures. While findings from previous studies on mtDNA copy number (mtDNAcn) and lung cancer risk have been mixed, mtDNA fraction with breaks (mtDNAfb) has recently emerged as a potential marker of oxidative stress and mitochondrial integrity. We investigated associations between prediagnostic mtDNAfb, mtDNAcn, and lung cancer risk in never-smoking women in the prospective Shanghai Women's Health Study (SWHS). Methods This nested case-control study included 789 incident lung cancer cases and 789 controls individually matched on birth year and blood collection date from the SWHS, a prospective cohort of 74,942 women enrolled between 1996 and 2000. DNA was extracted from white blood cells or buccal cells, and mtDNAfb was quantified using a high-throughput qPCR assay comparing amplification signals from TaqI-treated (digested) and untreated samples. Relative mtDNAcn was derived from qPCR measurements normalized to a reference gene. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of mtDNAfb and mtDNAcn with lung cancer risk, adjusting for age, body mass index, and assay plate. Sensitivity analyses further controlled for education, environmental tobacco smoke exposure, family history of lung cancer, and mutual adjustment for mtDNAfb and mtDNAcn. Interaction between mtDNAfb and mtDNAcn was tested on a multiplicative scale. Results We observed higher mtDNAfb was associated with lower risk of lung cancer with participants in the highest mtDNAfb tertile having 34% lower odds compared with those in the lowest tertile ( p trend = 0.026). No independent association was observed for mtDNAcn; however, a multiplicative interaction between mtDNAfb and mtDNAcn was identified ( p interaction = 8.3 × 10⁻⁶) where the association between mtDNAfb and lung cancer was more pronounced among participants with low mtDNAcn (OR = 0.47, 95% CI: 0.29-0.78) than those with high mtDNAcn (OR = 1.02, 95% CI: 0.58-1.79). Conclusions Lower mtDNAfb was associated with increased lung cancer risk among never-smoking women, particularly among women with low mtDNAcn, suggesting possible pathologic reductions in mitochondrial biogenesis and functioning, and consequently, reduced innate immune activation. These findings provide novel insights into mitochondrial dysfunction as a potential mechanism underlying lung cancer in never-smokers and warrant replication and mechanistic investigation in future studies.
利益披露 Disclosure
B. Blechter, None..
E. Francies, None..
R. Cawthon, None.