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J Thorac Cardiovasc Surg 2010;139:189-197
© 2010 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

The role of mitochondrial DNA alterations in esophageal squamous cell carcinomas

Chen-Sung Lin, MDa,d,e, Shi-Chuan Chang, MD, PhDa,b,f, Liang-Shun Wang, MDa,b,h, Teh-Ying Chou, MD, PhDa,g, Wen-Hu Hsu, MDa,e, Yu-Chung Wu, MDa,e, Yau-Huei Wei, PhDa,c,*

a Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan
b Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei 112, Taiwan
c Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan
d Division of Thoracic Surgery, Department of Surgery, Keelung Hospital, Department of Health, Executive Yuan, Keelung 201, Taiwan
e Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
f Department of Chest, Taipei Veterans General Hospital, Taipei 112, Taiwan
g Division of Surgical Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
h Division of Thoracic Surgery, Department of Surgery, En Chu Kong Hospital, Taipei 237, Taiwan

Received for publication September 8, 2008; revisions received March 26, 2009; accepted for publication April 12, 2009.

* Address for reprints: Yau-Huei Wei, PhD, Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan. (Email: joeman{at}ym.edu.tw).

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.

Abbreviations and Acronyms ANOVA = analysis of variance; ESCC = esophageal squamous cell carcinoma; mtDNA = mitochondrial DNA; nDNA = nuclear DNA; np = nucleotide position; PCR = polymerase chain reaction






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