Genetic variants in the circadian rhythm pathway as indicators of prostate cancer progression

Chia-Cheng Yu†,
Lih-Chyang Chen†,
Chih-Yung Chiou†,
Yu-Jia Chang,
Victor C. Lin,
Chao-Yuan Huang,
I-Ling Lin,
Ta-Yuan Chang,
Te-Ling Lu,
Cheng-Hsueh Lee,
Shu-Pin HuangEmail author and
Bo-Ying BaoEmail author

†Contributed equally

Cancer Cell International201919:87

https://doi.org/10.1186/s12935-019-0811-4

Received: 16 November 2018
Accepted: 1 April 2019
Published: 5 April 2019

Abstract

Background

To determine the association between circadian pathway genetic variants and the risk of prostate cancer progression.

Methods

We systematically evaluated 79 germline variants in nine circadian pathway genes in a cohort of 458 patients with localized prostate cancer as the discovery phase. We then replicated the significant findings in another cohort of 324 men with more advanced disease. The association of each variant with prostate cancer progression was evaluated by a log-rank test and Cox regression.

Results

A single nucleotide polymorphism of the neuronal PAS domain protein 2 (NPAS2) gene (rs6542993 A>T) was found to be associated with a significantly higher risk of disease progression in both localized (P = 0.001) and advanced (P = 0.039) prostate cancer cases. In silico analysis revealed decreased expression levels of NPAS2 in carriers of the T allele of rs6542993 compared with those carrying the A allele. Consistently, downregulation of NPAS2 expression was associated with more aggressive prostate cancer and poor progression-free survival (log-rank P = 0.002).