Abstract
BackgroundThe roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer.MethodsThe entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations.ResultsFourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64%) were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status.ConclusionOur results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.
Highlights
The roles of mitochondria in energy metabolism, the generation of reactive oxygen species (ROS), aging, and the initiation of apoptosis have implicated their importance in tumorigenesis [2]
Somatic mitochondrial DNA (mtDNA) mutations in esophageal primary tumors To test if somatic mtDNA mutation is a general phenomenon in esophageal cancer and to characterize the muta
Several novel missense mutations at both germline and somatic levels are likely to have an effect on mitochondrial function
Summary
In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer. The major function of mitochondria is to produce energy to support cellular activities through the oxidative phosphorylation pathway. During this process reactive oxygen species (ROS) are generated. Due to the lack of protective histone proteins and the close vicinity, mtDNA is an easy target for oxidative DNA damage by ROS. The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis [2]
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