Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer

BACKGROUND: Circadian positive feedback loop (CPFL) genes (CLOCK, BAML1, and NPAS2) have been implicated in cancer initiation and progression. The purpose of this study was to explore the effects of single‐nucleotide polymorphisms (SNPs) in CPFL genes on prognosis of gastric cancer (GC) patients. METHODS: Nine functional SNPs from the three CPFL genes were genotyped in a cohort of 704 GC patients undergoing resection. Multivariate Cox regression model and Kaplan‐Meier curve were used for prognosis analysis. RESULTS: Among the nine SNPs, rs11133399 in CLOCK, rs1044432 and rs2279284 in BAML1 were significantly associated with GC overall survival and recurrence‐free survival. The unfavorable genotypes of these SNPs showed a cumulative effect on GC prognosis. Multivariate assessment model indicated that these SNPs, in conjunction with clinical variables, enhanced the power to predict GC prognosis. In addition, survival tree analysis revealed the genotype of rs11133399 as a primary risk factor contributing to the prognosis of GC patients. Functional assays showed that the G allele in rs11133399 significantly enhanced luciferase reporter activity than A allele. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, suggesting that this SNP might affect the prognosis of GC through its influence on the expression of CLOCK gene. CONCLUSIONS: Our data indicate that SNPs in CPFL genes might contribute to the clinical outcome of GC through their impact on gene expression. Further studies are needed to elucidate its underlying molecular mechanisms.