Objective: The study objective was to evaluate the roles of mitochondrial DNA alterations in esophageal squamous cell carcinoma, with emphasis on the changes in the copy number and D310 variants of mitochondrial DNA. Methods: Paired samples microdissected from esophageal muscles, noncancerous esophageal mucosa, cancerous esophageal squamous cell carcinoma nests, and metastatic lymph nodes of 72 patients with esophageal squamous cell carcinoma were subjected to DNA extraction. The copy number and D310 variants of mitochondrial DNA were determined by quantitative real-time polymerase chain reaction and direct sequencing, respectively. Results: Fifty-six patients (77.8%) with somatic D310 mutations had lower survival probability (P = .027). From noncancerous esophageal mucosa to cancerous esophageal squamous cell carcinoma nests and metastatic lymph nodes, the D310 variants were decreased from 2.2 to 1.7 and 1.5, respectively, with a trend to homoplasmy (P = .0009). Concurrently, the mitochondrial DNA copy number was increased from 0.159 to 0.192 and 0.206, respectively, (P = .024), especially in cigarette smokers (P = .014) and heavy wine drinkers (P = .005). Notably, a decrease in D310 variants (1.5, P < .001) and an increase in the incidence of the homoplasmic D310 pattern (P = .005) were observed in the matched esophageal muscle tissues. Among the 56 esophageal squamous cell carcinoma cancer nests with somatic D310 mutations, 51 (91.1%) had D310 variants in association with their corresponding noncancerous esophageal mucosa, including 36 (64.3%) fully related and 15 (26.8%) partially related pairs. Conclusion: We demonstrated that somatic D310 mutations and increase in the copy number of mitochondrial DNA are of clinical importance in esophageal squamous cell carcinoma. We also propose a model of DNA instability and clonal expansion during the carcinogenesis and progression of esophageal squamous cell carcinoma from the viewpoint of mitochondrial DNA transmission.
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