Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients

Circadian negative feedback loop (CNFL) genes play important roles in cancer development and progression. To evaluate the effects of single nucleotide polymorphisms (SNPs) in CNFL genes on the survival of GC patients, 13 functional SNPs from 5 CNFL genes were genotyped in a cohort of 1030 resected GC patients (704 in the training set, 326 in the validation set) to explore the association of SNPs with overall survival (OS). Among the 13 SNPs, three SNPs (rs1056560 in CRY1, rs3027178 in PER1 and rs228729 in PER3) were significantly associated with OS of GC in the training set, and verified in the validation set and pooled analysis. Furthermore, a dose-dependent cumulative effect of these SNPs on GC survival was observed, and survival tree analysis showed higher order interactions between these SNPs. In addition, protective effect conferred by adjuvant chemotherapy (ACT) on GC was observed in patients with variant alleles (TG/GG) of rs1056560, but not in those with homozygous wild (TT) genotype. Functional assay suggested rs1056560 genotypes significantly affect CRY1 expression in cancer cells. Our study presents that SNPs in the CNFL genes may be associated with GC prognosis, and provides the guidance in selecting potential GC patients most likely responsive to ACT.