1. Department of Liver Surgery, Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, 200032, China
2. Department of Surgery, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, 201199, China.
3. Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Zhongshan Hospital, Fudan University, Shanghai, 201199, China.
4. Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
*These authors contributed equally to this study.
Introduction: The WW domain-containing oxidoreductase (WWOX), widely expressed in human tissues, is considered as a tumor suppressor gene and plays an important role in the incidence and progression of human cancer, HCC included. This study was to investigate the correlation between single nucleotide polymorphisms (SNPs) of the WWOX gene and the prognosis of hepatocellular carcinoma (HCC) patients.
Materials and Methods: After a total of 152 HCC patients were recruited, 8 cases with tumor recurrence within 2-years after operation and 8 cases without recurrence were selected randomly for SNP genotyping and screening using Affymetrix Array 6.0. And then we confirmed candidate SNPs in the remaining 136 patients by time-of-flight mass spectrometry (TOF-MS).
Results: In total, 32 SNPs were screened and identified as candidate SNPs with one SNP in particular, (rs9926344), being further verified to be valuable. We found that AA+AG genotype and A allele of WWOX rs9926344 were significantly associated with recurrent risk of HCC (p=0.002 and p=0.001, respectively). The Kaplan-Meier curve showed that patients carrying rs9926344 AA +AG genotype had poor RFS (P=0.004) and OS (P=0.005) compared to those carrying GG genotypes. The multivariate COX regression analysis showed that the AA+AG genotype were an independent prognostic factor for tumor recurrence (HR 1.787, 95% CI 1.042-3.064, P=0.035). Furthermore, IHC analysis showed that the WWOX protein down-regulation is more frequent in patients with AG genotype compared to those with GG genotype (P=0.023).
Conclusion: Our findings indicate that WWOX rs9926344 polymorphism is positively correlated with tumor recurrence and can be used as an independent prognostic marker for HCC patients after operation.
Keywords: hepatocellular carcinoma, WWOX gene, single nucleotide polymorphism, recurrence, prognosis