Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer

Xu,Hui; He,Wei; Jiang,Huan-Gang; Zhao,Hong; Peng,Xiao-Hong; Wei,Yue-Hua; Wei,Jing-Ni; Xie,Cong-Hua; Liang,Chen; Zhong, Ya-Hua; Zhang,Gong; Deng,Di; Zhou,Yun-Feng; Zhou,Fu-Xiang

doi:10.3892/or.2013.2783

Prognostic value of mitochondrial DNA content and G10398A polymorphism in non-small cell lung cancer

Authors:
- Hui Xu
- Wei He
- Huan-Gang Jiang
- Hong Zhao
- Xiao-Hong Peng
- Yue-Hua Wei
- Jing-Ni Wei
- Cong-Hua Xie
- Chen Liang
- Ya-Hua Zhong
- Gong Zhang
- Di Deng
- Yun-Feng Zhou
- Fu-Xiang Zhou
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Affiliations: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuchang, Wuhan, Hubei 430071, P.R. China
Published online on: October 3, 2013 https://doi.org/10.3892/or.2013.2783
Pages: 3006-3012

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Abstract

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality worldwide. Mitochondrial dysfunction has been postulated to render cancer cells resistant to apoptosis based on the Warburg hypothesis. However, few studies have investigated the prognostic value of mitochondrial DNA (mtDNA) content and G10398A polymorphism in NSCLC patients. mtDNA copy number and G10398A polymorphism in 128 NSCLC tissue samples were assessed by real-time PCR (RT-PCR) and PCR-RFLP respectively, and their relationship to prognosis were analyzed by survival analysis and Cox proportional hazards model. In vitro, an mtDNA deletion A549 ρ0 cell model was utilized to assess the function of mtDNA on radiosensitivity. Cell cycle distribution and reactive oxygen species (ROS) were analyzed to elucidate the potential mechanisms. For the whole group, the median follow-up time and overall survival time were 22.5 and 23.4 months, respectively. Patients with high mtDNA content had a marginally longer survival time than patients with low mtDNA content (P=0.053). Moreover, patients with high mtDNA content plus 10398G had a significantly longer overall survival time compared with those having low mtDNA content plus 10398A (47 vs. 27 months, P<0.05). In addition, multivariate analysis showed that stage and low mtDNA content plus 10398A were the two most independent prognostic factors. In vitro, the A549 ρ0 cells showed more resistance to radiation than ρ+ cells. Following radiation, ρ0 cells showed delayed G2 arrest and lower ROS level as compared to ρ+ cells. In conclusion, the present study suggests that in patients with NSCLC, low mtDNA content plus 10398A could be a marker of poor prognosis which is associated with resistance to anticancer treatment caused by low mtDNA content plus 10398A polymorphism resulting in mitochondrial dysfunction.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2010. View Article : Google Scholar
2	Siegel R, Ward E, Brawley O and Jemal A: Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 61:212–236. 2011. View Article : Google Scholar : PubMed/NCBI
3	Peng J, Yang LX, Zhao XY, Gao ZQ, Yang J, et al: VCP gene variation predicts outcome of advanced non-small-cell lung cancer platinum-based chemotherapy. Tumour Biol. 34:953–961. 2013. View Article : Google Scholar : PubMed/NCBI
4	Sánchez-Aragó M, Chamorro M and Cuezva JM: Selection of cancer cells with repressed mitochondria triggers colon cancer progression. Carcinogenesis. 31:567–576. 2010.PubMed/NCBI
5	Chatterjee A, Dasgupta S and Sidransky D: Mitochondrial subversion in cancer. Cancer Prev Res (Phila). 4:638–654. 2011. View Article : Google Scholar
6	Wang H and Dai J: Changes on mitochondrial DNA content in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 14:141–145. 2011.(In Chinese).
7	Lin CS, Wang LS, Tsai CM and Wei YH: Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy. Interact Cardiovasc Thorac Surg. 7:954–958. 2008. View Article : Google Scholar : PubMed/NCBI
8	Choi SJ, Kim SH, Kang HY, Lee J, Bhak JH, et al: Mutational hotspots in the mitochondrial genome of lung cancer. Biochem Biophys Res Commun. 407:23–27. 2011. View Article : Google Scholar : PubMed/NCBI
9	Pezzotti A, Kraft P, Hankinson SE, Hunter DJ, Buring J and Cox DG: The mitochondrial A10398G polymorphism, interaction with alcohol consumption, and breast cancer risk. PloS One. 4:e53562009. View Article : Google Scholar : PubMed/NCBI
10	Jin X, Zhang J, Gao Y, Ding K, Wang N, et al: Relationship between mitochondrial DNA mutations and clinical characteristics in human lung cancer. Mitochondrion. 7:347–353. 2007. View Article : Google Scholar : PubMed/NCBI
11	Malik AN, Shahni R, Rodriguez-de-Ledesma A, Laftah A and Cunningham P: Mitochondrial DNA as a non-invasive biomarker: accurate quantification using real time quantitative PCR without co-amplification of pseudogenes and dilution bias. Biochem Biophys Res Commun. 412:1–7. 2011. View Article : Google Scholar : PubMed/NCBI
12	Kawada I, Soejima K, Watanabe H, Nakachi I, Yasuda H, et al: An alternative method for screening EGFR mutation using RFLP in non-small cell lung cancer patients. J Thorac Oncol. 3:1096–1103. 2007. View Article : Google Scholar : PubMed/NCBI
13	Datta S, Majumder M, Biswas NK, Sikdar N and Roy B: Increased risk of oral cancer in relation to common Indian mitochondrial polymorphisms and Autosomal GSTP1 locus. Cancer. 110:1991–1999. 2007. View Article : Google Scholar : PubMed/NCBI
14	Yu M: Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci. 89:65–71. 2011. View Article : Google Scholar : PubMed/NCBI
15	Yu M: Somatic mitochondrial DNA mutations in human cancers. Adv Clin Chem. 57:99–138. 2012. View Article : Google Scholar : PubMed/NCBI
16	Kim MM, Clinger JD, Masayesva BG, Ha PK, Zahurak ML, et al: Mitochondrial DNA quantity increases with histopathologic grade in premalignant and malignant head and neck lesions. Clin Cancer Res. 10:8512–8515. 2004. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Liu VW, Xue WC, Cheung AN and Ngan HY: Association of decreased mitochondrial DNA content with ovarian cancer progression. Br J Cancer. 95:1087–1091. 2006. View Article : Google Scholar : PubMed/NCBI
18	Yamada S, Nomoto S, Fujii T, Kaneko T, Takeda S, et al: Correlation between copy number of mitochondrial DNA and clinico-pathologic parameters of hepatocellular carcinoma. Eur J Surg Oncol. 32:303–307. 2006. View Article : Google Scholar : PubMed/NCBI
19	Xing J, Chen M, Wood CG, Lin J, Spitz MR, et al: Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst. 100:1104–1112. 2008. View Article : Google Scholar : PubMed/NCBI
20	Hsu CW, Yin PH, Lee HC, Chi CW and Tseng LM: Mitochondrial DNA content as a potential marker to predict response to anthracycline in breast cancer patients. Breast J. 16:264–270. 2010. View Article : Google Scholar : PubMed/NCBI
21	Wu CW, Yin PH, Hung WY, Li AF, Li SH, et al: Mitochondrial DNA mutations and mitochondrial DNA depletion in gastric cancer. Genes Chromosomes Cancer. 44:19–28. 2005. View Article : Google Scholar : PubMed/NCBI
22	Canter JA, Kallianpur AR, Parl FF and Millikan RC: Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res. 65:8028–8033. 2005.
23	Kulawiec M, Owens KM and Singh KK: mtDNA G10398A variant in African-American women with breast cancer provides resistance to apoptosis and promotes metastasis in mice. J Hum Genet. 54:647–654. 2009. View Article : Google Scholar : PubMed/NCBI
24	Anoopkumar-Dukie S, Conere T, Sisk GD and Allshire A: Mitochondrial modulation of oxygen-dependent radiosensitivity in some human tumour cell lines. Br J Radiol. 82:847–854. 2009. View Article : Google Scholar : PubMed/NCBI
25	Armand R, Channon JY, Kintner J, White KA, Miselis KA, et al: The effects of ethidium bromide induced loss of mitochondrial DNA on mitochondrial phenotype and ultrastructure in a human leukemia T-cell line (MOLT-4 cells). Toxicol Appl Pharmacol. 196:68–79. 2004. View Article : Google Scholar : PubMed/NCBI
26	Yu M, Shi Y, Wei X, Yang Y, Zhou Y, et al: Depletion of mitochondrial DNA by ethidium bromide treatment inhibits the proliferation and tumorigenesis of T47D human breast cancer cells. Toxicol Lett. 170:83–93. 2007. View Article : Google Scholar : PubMed/NCBI
27	Park SY, Chang I, Kim JY, Kang SW, Park SH, et al: Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem. 279:7512–7520. 2004. View Article : Google Scholar : PubMed/NCBI
28	Cloos CR, Daniels DH, Kalen A, Matthews K, Du J, et al: Mitochondrial DNA depletion induces radioresistance by suppressing G2 checkpoint activation in human pancreatic cancer cells. Radiat Res. 171:581–587. 2009. View Article : Google Scholar : PubMed/NCBI
29	Kawamura SD, Takai K, Watanabe J, Hayashi J, Hayakawa K and Akashi M: Role of mitochondrial DNA in cells exposed to irradiation: generation of reactive oxygen species (ROS) is required for G2 checkpoint upon irradiation. J Health Sci. 51:385–393. 2005. View Article : Google Scholar
30	Kulawiec M, Ayyasamy V and Singh KK: p53 regulates mtDNA copy number and mitocheckpoint pathway. J Carcinog. 8:82009. View Article : Google Scholar : PubMed/NCBI