title: Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma.
abstract: Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.
authors.affiliation: Institute of Pharmacy, Pharmaceutical College of Henan University, Kaifeng, Henan, China.
authors.forename: Shaogui
authors.initials: S
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yousheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xingchun
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Jiaze
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Interventional Radiology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Pain treatment, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hushan
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002681:China; D002952:Citric Acid Cycle / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012008:Recurrence; D012307:Risk Factors; D016019:Survival Analysis