Variable copy number of mitochondrial DNA (mtDNA) predicts worse prognosis in advanced gastric cancer patients

Abstract

Background: Change of mitochondrial DNA (mtDNA) copy number is widely reported in various human cancers, including gastric cancer, and is considered to be an important hallmark of cancers. However, there is remarkably little consensus on the value of variable mtDNA content in the prognostic evaluation of this cancer.

Methods: Using real-time quantitative PCR approach, we examined mtDNA copy number in a cohort of gastric cancers and normal gastric tissues, and explored the association of variable mtDNA content with clinical outcomes of gastric cancer patients.

Results: Our data showed that the majority of gastric cancer patients had low mtDNA content as compared to control subjects although the relative mean mtDNA content was higher in the former than the latter. Moreover, we found that variable mtDNA content was strongly associated with lymph node metastasis and cancer-related death of the patients with late-stage tumors. Notably, variable mtDNA content did not affect overall survival of gastric cancer patients, however, we found that increased mtDNA content was associated with poor survival in the patients with late-stage tumors.

Conclusion: In this study, we demonstrated that variable mtDNA content markedly increased the risk of lymph node metastasis and high mortality of the patients with late-stage tumors. Additionally, we found a strong link between increased mtDNA content and worse survival of the patients with late-stage tumors. Taken together, variable mtDNA content may be a valuable poor prognostic factor for advanced gastric cancer patients.

Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1344721463103353.

Figure 1

Copy number of mtDNA corresponding to each individual case of gastric cancers and normal gastric tissues (circle). Real-time quantitative PCR assay was performed to analyze mtDNA copy number in a cohort of gastric cancers and normal gastric tissues. Horizonal lines represent mean ± S.E. Details are as described in Methods. T, tumor tissues; N, normal gastric tissues.

Figure 2

Association of mtDNA copy number with clinicopathological characteristics in gastric cancer. Copy number of mtDNA was analyzed using real-time quantitative PCR approach. The circle represents mtDNA copy number of each case of gastric cancers. Horizonal lines represent mean ± S.E. Sample means were compared using the Mann–Whitney U test. Details are as described in Methods. F, female; M, male; GC, gastric cardia; GA, gastric antrum; GB, gastric body; Well, well/moderate differentiation; Poor, poor/undifferentiation; N, non-lymph node metastasis; Y, lymph node metastasis; ES, early-stage; LS, late-stage.

Figure 3

The effect of variable mtDNA content on poor survival of gastric cancer patients. Kaplan-Meier analysis of survival was performed according to copy number variations of mtDNA in a large cohort of gastric cancers. Kaplan-Meier survival curves show that variable (decreased or increased) mtDNA content was not associated with overall survival of the patients. However, when the data were stratified further based on the TNM tumor stage, increased mtDNA content (>5.35 copies) was strongly associated with worse survival in the patients who had late-stage tumors.