Mitochondrial DNA breaks and copy number and the risk of lung cancer in the Shanghai Women’s Health Study

Background Lung cancer remains the leading cause of cancer mortality worldwide, and approximately one-quarter of cases occur among individuals who never smoke. Mitochondria are highly susceptible to oxidative damage from environmental stressors, which can alter mitochondrial DNA (mtDNA) copy number (mtDNAcn) and induce mtDNA fragmentation. While prior studies of mtDNAcn and lung cancer have yielded inconsistent results, the role of mtDNA fragmentation has not been examined. Methods We conducted a nested case-control study within the prospective Shanghai Women's Health Study, including 789 incident lung cancer cases among never-smoking women and 789 individually matched controls. Prediagnostic whole-blood samples were analyzed for mtDNA fraction with breaks (mtDNAfb) and mtDNAcn using high-throughput quantitative PCR assays. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer risk associated with mtDNAfb and mtDNAcn, adjusting for age, body mass index, and plate. We further assessed an interaction between mtDNAfb and mtDNAcn. Results Higher mtDNAfb was inversely associated with lung cancer risk, with 34% lower odds among participants with high mtDNAfb compared with those with low mtDNAfb (OR=0.66, 95% CI: 0.51-0.85). Notably, a significant interaction was observed between mtDNAfb and mtDNAcn (P-interaction=8.3×10⁻⁶), with a stronger inverse association between mtDNAfb and lung cancer among women with low mtDNAcn. Conclusions Lower mtDNA fragmentation is associated with increased lung cancer risk among never-smoking women, particularly among those with low mtDNA copy number. Impact MtDNA fragmentation may represent a novel biomarker of impaired mitochondrial response to oxidative stress relevant to lung carcinogenesis.