Abstract
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.
Highlights
IntroductionA number of SNPs associated with cancer risk and prognosis have been identified in human CNFL genes, as documented by large population-based studies[13]
Our data showed that the risk of death for Gastric cancer (GC) was significantly increased as the stage increased in a dose-response manner among training set, validation set and pooled analysis, and a similar result was obtained for risk of recurrence
We investigated the association of thirteen functional SNPs in several CNFL genes with the prognosis of GC patients by a two-stage analysis of training and validation sets
Summary
A number of SNPs associated with cancer risk and prognosis have been identified in human CNFL genes, as documented by large population-based studies[13]. One recent study has reported that four functional SNPs in CNFL genes are associated with shorter OS and relapse-free survival(RFS) in HCC patients after radical surgery[16]. The association between the functional SNPs in CNFL genes and the clinical outcomes of GC patients remains not to be determined. To test the hypothesis that the polymorphisms of CNFL genes may affect the prognosis and clinical outcome of GC, we assessed the effects of thirteen functional SNPs in PER1, PER2, PER3, CRY1 and CRY2 on survival time of 1030 Chinese GC patients (704 in the training set, 326 in the independent validation set) who received radical resection treatment. To the best of our knowledge, this is the first investigation of the association between SNPs in CNFL genes and the clinical outcome of GC
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