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.
Highlights
Hepatocellular carcinoma (HCC) is one leading cause of cancer death worldwide[1]
All three single nucleotide polymorphisms (SNPs) in SDHD gene were significantly associated with the increased HCC recurrence risk under dominant model
SNPs rs1414493 in fumarate hydratase (FH) gene and rs11540478 in IDH2 gene were significantly associated with the decreased HCC overall recurrence risk under dominant (HR = 0.77, 95%CI 0.61–0.97, P = 0.030) and recessive (HR = 0.25, 95%CI 0.09–0.68, P = 0.007) models, respectively
Summary
The current curative therapies for HCC are limited to early stage diseases with first-line treatments of surgical resection and liver transplantation. The recurrence and metastasis occur frequently after curative surgical treatment [2]. It has been estimated that the 5-year recurrence rate is frequently higher than 70% in HCC patients with early stage disease after curable treatments such as surgical resection and ablation, significant low recurrence rate (
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