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Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection

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Abstract

Previous studies have demonstrated that circadian negative feedback loop genes play an important role in the development and progression of many cancers. However, the associations between single-nucleotide polymorphisms (SNPs) in these genes and the clinical outcomes of hepatocellular carcinoma (HCC) after surgical resection have not been studied so far. Thirteen functional SNPs in circadian genes were genotyped using the Sequenom iPLEX genotyping system in a cohort of 489 Chinese HCC patients who received radical resection. Multivariate Cox proportional hazards model and Kaplan–Meier curve were used for the prognosis analysis. Cumulative effect analysis and survival tree analysis were used for the multiple SNPs analysis. Four individual SNPs, including rs3027178 in PER1, rs228669 and rs2640908 in PER3 and rs3809236 in CRY1, were significantly associated with overall survival (OS) of HCC patients, and three SNPs, including rs3027178 in PER1, rs228729 in PER3 and rs3809236 in CRY1, were significantly associated with recurrence-free survival (RFS). Moreover, we observed a cumulative effect of significant SNPs on OS and RFS (P for trend < 0.001 for both). Survival tree analysis indicated that wild genotype of rs228729 in PER3 was the primary risk factor contributing to HCC patients’ RFS. Our study suggests that the polymorphisms in circadian negative feedback loop genes may serve as independent prognostic biomarkers in predicting clinical outcomes for HCC patients who received radical resection. Further studies with different ethnicities are needed to validate our findings and generalize its clinical utility.

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Acknowledgments

This work was supported by Program for New Century Excellent Talents in University, grants 81201583 and 81171966 from the National Natural Science Foundation, grant S2011GR0239 from the International S&T Cooperation Program and grant 2011ZX09307-001-04 from National Key Scientific and Technological Project of China.

Conflict of interest

The authors have declared that no competing interests exist.

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Authors and Affiliations

  1. Department of Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China

    Zhaohui Zhang & Jianwei Bi

  2. State Key Laboratory of Cancer Biology, Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, Shaanxi, China

    Fei Ma, Yibing Chen & Xiaoyan Wang

  3. Department of General Surgery, Huaihai Hospital, Xuzhou Medical College, Xuzhou, Jiangsu, China

    Zhaohui Zhang & Feng Zhou

  4. Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Hongxin Zhang

  5. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, USA

    Yong Zhu

  6. Josephine Ford Cancer Center, Department of Internal Medicine, Henry Ford Health System, Tech Town, 440 Burroughs, Detroit, MI, 48202, USA

    Yiguan Zhang

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  1. Zhaohui Zhang
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  2. Fei Ma
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  3. Feng Zhou
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Correspondence to Jianwei Bi or Yiguan Zhang.

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Zhaohui Zhang and Fei Ma have contributed equally to this work.

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Zhang, Z., Ma, F., Zhou, F. et al. Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection. Med Oncol 31, 179 (2014). https://doi.org/10.1007/s12032-014-0179-1

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