Low circadian clock genes expression in cancers: A meta-analysis of its association with clinicopathological features and prognosis

Per1, Per2, Per3, Cry1, Cry2, Bmal1, Npas2 and CLOCK genes are the eight core circadian clock genes. Low expression of these circadian clock genes plays an important role in the progression of cancers. However, its clinicopathological and prognostic value in patients with cancers remains controversial and inconclusive. We performed a meta-analysis of studies assessing the clinicopathological and prognostic significance of low expression of these genes in cancers.

Relevant studies were searched from the Cochrane Central Register of Controlled Trials, Embase, EBSCO, Ovid, PubMed, Science Direct, Wiley Online Library database, CNKI and Wan Fang database. The meta-analysis was performed by using STATA version 12 software. A random-effect model was employed to evaluate all pooled hazard ratios (HRs) and odd ratios (ORs).

A total of 36 studies comprising 7476 cases met the inclusion criteria. Meta-analysis suggested that low expression of Per1 was associated with poor differentiation (Per1: OR=2.30, 95%CI: 1.36∼3.87, P=0.002) and deeper invasion depth (Per1: OR=2.12, 95%CI: 1.62∼2.77, Ρ<0.001); low Per2 expression was correlated with poor differentiation (Per2: OR=2.41, 95%CI: 1.53∼3.79, Ρ<0.001), worse TNM stage (Per2:OR=3.47, 95%CI: 1.88∼6.42, P<0.001) and further metastasis (Per2:OR=2.35, 95%CI: 1.35∼4.11, Ρ=0.003). Furthermore, the results revealed that low expressions of Per1 and Per2 were also correlated with poor overall survival of cancers (Per1: HR=1.35, 95%CI: 1.06∼1.72, P=0.014; Per2: HR=1.43, 95%CI: 1.10∼1.85, P=0.007). Subgroup analysis indicated that low Per1 and Per2 expressions were especially associated with poor prognosis of gastrointestinal caners (Per1: HR=1.33, 95%CI: 1.14∼1.55, Ρ<0.001, Ι2=4.2%; Per2: HR=1.62, 95%CI: 1.25∼2.18, P<0.001, I2=0.0%).

Our study suggested that low Per1, Per2 and Npas2 expression played a distinct and crucial role in progression of cancers. Low expressions of Per1 and Per2 could serve as unfavorable indicators for cancers prognosis, especially for gastrointestinal cancers.