title: Functional polymorphisms of circadian positive feedback regulation genes and clinical outcome of Chinese patients with resected colorectal cancer.
abstract: BACKGROUND
  Previous studies have demonstrated that circadian genes play a role in the development and progression of many cancers. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in circadian genes on recurrence and survival of colorectal cancer (CRC) patients.
  
  
  METHODS
  Nine functional SNPs in 3 genes (CLOCK, NPAS2, and BMAL1) on the circadian positive feedback loop were selected and genotyped using the Sequenom iPLEX genotyping system in a cohort of 411 resected Chinese CRC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis.
  
  
  RESULTS
  The authors identified 2 SNPs in the CLOCK gene to be significantly associated with CRC overall survival. SNP rs3749474 exhibited a significant association with survival of CRC patients in the additive model (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.37-0.81; P = .003). In addition, patients carrying the heterozygous variant of rs1801260 had significantly increased overall survival compared with those carrying homozygous wild-type genotype (HR, 0.31; 95% CI, 0.11-0.88; P = .03). Findings from functional assay provided further biological support for these significant associations. Stratified analysis found no modifying effect of chemotherapy on the prognostic significance of both SNPs. Moreover, we observed cumulative effects of these 2 SNPs on CRC overall survival (P for trend = .01). Compared with patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 2.92-fold increased risk of death (P = .03).
  
  
  CONCLUSIONS
  The results suggest for the first time that CLOCK gene polymorphisms may serve as an independent prognostic marker for CRC patients.
authors.affiliation: Department of General Surgery, Tangdu Hospital, Xi'an, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.forename: Xianli
authors.initials: X
authors.lastname: He
authors.forename: Hanqiang
authors.initials: H
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Tianbo
authors.initials: T
authors.lastname: Jin
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Falin
authors.initials: F
authors.lastname: Qu
authors.forename: Yunming
authors.initials: Y
authors.lastname: Li
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Bao
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Chen
authors.forename: Jinliang
authors.initials: J
authors.lastname: Xing
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000601:surgery*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D056926:CLOCK Proteins / Q000235:genetics*; D002681:China; D057906:Circadian Clocks / Q000235:genetics; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery*; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality / Q000601:surgery; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D009419:Nerve Tissue Proteins; C538960:BMAL1 protein, human; C104264:NPAS2 protein, human; C538943:CLOCK protein, human