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

Yibing Chen,Dandan Wang,Yucen Song,Lin Lü,Zhengzhi Zou,Wei Du,Xiaofei Zhang,Falin Qu,Juqin Dong,Zhihui Jiao

doi:10.1002/cam4.2050

Abstract

BackgroundCircadian 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.MethodsNine 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.ResultsAmong 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.ConclusionsOur 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.

Highlights

Gastric cancer (GC) is one of the most common malignancies worldwide, with more than 950 000 newly diagnosed cases and 720 000 deaths each year.[1]
Neutrophils are enriched predominantly in the invasive margin of gastric cancer (GC) tissues and increased neutrophil counts in the peripheral blood are significantly associated with poor prognosis in GC patients.[21]
We evaluated the effects of nine functional single‐nucleotide polymorphisms (SNPs) in the three Circadian positive feedback loop (CPFL) genes (CLOCK, NPAS2, and BMAL1) on the prognosis of a cohort of Chinese GC patients

Summary

Introduction

Gastric cancer (GC) is one of the most common malignancies worldwide, with more than 950 000 newly diagnosed cases and 720 000 deaths each year.[1]. Previous studies have demonstrated that abnormal expression of circadian clock genes is associated with the prognosis of cancer patients.[6]. These findings highlight the vital role of circadian clock genes in tumorigenesis and cancer developing. 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. Immunohistochemical analysis further demonstrated that the genotype of rs11133399 was significantly associated with the expression level of CLOCK in GC tissues, Yibing Chen and Dandan Wang contributed to this work

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