title: Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer.
abstract: BACKGROUND
  Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the outcome. Metabolic reprogramming is a hallmark of cancer, including the alterations of tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in NSCLC.
  
  
  METHODS
  In this study, we genotyped 18 potentially functional SNPs in 7 genes belonging to 3 TCA cycle enzyme families (SDH, FH and IDH) using Sequenom iPLEX genotyping system in a cohort of 500 NSCLC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis.
  
  
  RESULTS
  Our results showed that SDHC gene: SNP rs12064957, IDH2 gene: SNP rs11540478 and FH gene: SNP rs1414493 were associated with overall survival (OS) and SDHA gene: SNP rs13173911, IDH2 gene: SNP rs4932158 were associated with recurrence-free survival (RFS) of NSCLC patients. Unfavorable genotypes of these SNPs showed a significant cumulative effect on OS and RFS of NSCLC patients (both P<0.001). Furthermore, survival tree analysis indicated that FH: rs1414493 was the primary risk factor contributing to OS of NSCLC patients and the IDH2: rs4932158 was the primary risk factor contributing to RFS of NSCLC patients.
  
  
  CONCLUSIONS
  Our data suggest that SNPs in TCA cycle key enzyme genes may serve as potential biomarkers to predict the outcomes of NSCLC. Further studies with different ethnicities are needed to validate our findings and generalize their clinical utility.
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Deyang
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Yousheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Breast Center, Tumor Hospital of Shaanxi Province, Xi'an 710061, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Li
authors.affiliation: Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: hushan.yang@jefferson.edu.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biologyand Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an710032, China. Electronic address: xingjinliang@163.com.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D002952:Citric Acid Cycle / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D040641:Quantitative Trait Loci; D012307:Risk Factors; D016896:Treatment Outcome
keywords: Fumarate hydratase; Isocitrate dehydrogenase; Non-small cell lung cancer; Prognosis; Single nucleotide polymorphisms; Succinate dehydrogenase; Tricarboxylic acid cycle