title: Functional polymorphisms of circadian negative feedback regulation genes are associated with clinical outcome in hepatocellular carcinoma patients receiving radical resection.
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.
authors.affiliation: Department of Surgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Ma
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Yibing
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Hongxin
authors.initials: H
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jianwei
authors.initials: J
authors.lastname: Bi
authors.forename: Yiguan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D056931:Cryptochromes / Q000235:genetics*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies / Q000379:methods; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D056950:Period Circadian Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C538963:CRY1 protein, human; D056931:Cryptochromes; C539022:PER1 protein, human; C512644:PER3 protein, human; D056950:Period Circadian Proteins