Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer
Introduction
Lung cancer is now the leading cause of cancer mortality for human, due to its high incidence, malignant behaviors and lack of effective treatment [1]. About 85% of lung cancer cases are non-small cell lung cancers (NSCLC), and there has been a significant increase in the incidence of NSCLC over the last two decades in China [2], [3]. Although great improvement of treatment, the prognosis of NSCLC remains very poor. The 5-year survival rate of NSCLC patients is only about 15% in USA and 9% in developing countries [4]. To date, very few biomarkers have been identified for risk assessment or prognosis predication of NSCLC patients. Therefore, there is an urgent need for prognostic biomarkers to further improve the clinical management of patients with NSCLC.
The tricarboxylic acid (TCA) cycle, which occurs in mitochondria, is a core pathway for the metabolism of sugars, lipids, and amino acids [5]. Recently, the roles of mitochondrial alterations in cancer come to general attention with the discovery of mutations in mitochondrial TCA cycle core genes, which mainly include succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase 1(IDH1) and IDH2 [6]. SDH which consists of four subunits, i.e. SDHA, SDHB, SDHC, and SDHD, is an component enzyme of the mitochondrial complex II contributing to the generation of ATP by oxidative phosphorylation. Inherited or somatic mutations in genes encoding subunits B, C, or D of SDH are associated with the development of pheochromocytoma and paraganglioma [7], [8], [9]. More recently, SDHB mutations have also been identified to be associated with renal cell carcinoma and papillary thyroid cancer [10]. Also, the decreased expression of SDHD gene has been reported in gastric and colon carcinoma [11]. FH functions as a homotetramer to catalyze the TCA cycle process (the hydration of fumarate to malate) following SDH [12]. Homozygous null mutations in FH gene are associated with multiple uterine leiomyomatas and aggressive forms of renal cell cancer [13]. Recent evidences suggest that germline mutations in FH gene are also associated with developing risks of breast, bladder and testicular cancers [14], [15]. The NADP+-dependant enzymes IDH1 and IDH2 mainly contribute to the production α-ketoglutarate and NADPH in the mitochondria, and play a vital role in cellular defense against reactive oxygen species through the reduction of glutathione [16]. Heterozygous missense somatic mutations in IDH1 and IDH2 genes have been observed in gliomas, chondromas and acute myeloid leukemia (AML) [17], [18], [19].
Single-nucleotide polymorphisms (SNPs) are easily detectable genetic variants as they can be analyzed from blood samples [20]. Thus, SNPs are attractive molecular markers for translational studies. Several SNPs have been found to be capable of predicting survival of NSCLC [21], [22], [23]. Considering that the important role of TCA pathway core genes in cancer progression [24], we hypothesize that SNPs in these genes may alter gene expression and/or protein activity, and have an effect on the prognosis of NSCLC cancers. To test this hypothesis, we selected 18 functional SNPs in the SDHA\B\C\D, IDH1, IDH2, FH genes and evaluated their associations with survival in a Chinese cohort of 500 patients diagnosed with NSCLC.
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Study population
We initially enrolled 556 NSCLC patients from July 2009 to December 2011 at the Department of Thoracic Surgery, Tangdu Hospital affiliated to the Fourth Military Medical University (FMMU), Xi’an, China. In the present study, we excluded 56 patients, including 17 who had incomplete clinical information or contact lost during the follow-up; 13 who died within 2 months after surgery; 17 with unresectable metastatic tumors; and 9 with recurrence within 1 month after surgery. As a result, 500 NSCLC
Distribution of patient characteristics and prognosis analysis
The study included 500 patients with resected NSCLC (Table 1). The median age at the time of diagnosis was 60 years (range, 27–86) for all patients. Among these patients, there were 268 (53.6%) squamous cell carcinomas and 146 (29.2%) adenocarcinomas. In addition, 86 (17.2%) patients had adenosquamous carcinoma, large cell carcinoma, carcinosarcoma or mucoepidermoid carcinoma. There were 390 males (78.0%) and 346 smokers (69.2%). There were more patients (56.2%) with early stage (stage I and
Discussion
In the present study, we assessed the associations of potential functional SNPs in genes encoding the three key enzymes of TCA cycle with the outcomes of NSCLC patients. We obtained three major findings as follows: 5 individual SNPs in SDHA, SDHC, FH, and IDH2 genes were significantly associated with patients’ survival; cumulative effect analysis demonstrated that the effects of these SNPs on OS and RFS of NSCLC patients showed a dose-dependent manner; survival tree analysis revealed that SNP
Conflict of interest statement
Authors declare that there is no competing interest.
Funding
This work was supported by Program for New Century Excellent Talents in University, grants 81402328 from the National Natural Science Foundation.
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Xu Guo and Deyang Li contributed equally to this work.