Epidemiology

Breast Cancer Research and Treatment

, Volume 120, Issue 3, pp 663-669

First online:

The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer

  • Chunhui YiAffiliated withDepartment of Epidemiology and Public Health, Yale University School of Medicine
  • , Lina MuAffiliated withDepartment of Epidemiology and Public Health, Yale University School of Medicine
  • , Irene A. Rigault de la LongraisAffiliated withDepartment of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin
  • , Olga SochircaAffiliated withDepartment of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin
  • , Riccardo ArisioAffiliated withDepartment of Pathology, S’Anna Hospital
  • , Herbert YuAffiliated withDepartment of Epidemiology and Public Health, Yale University School of Medicine
  • , Aaron E. HoffmanAffiliated withDepartment of Epidemiology and Public Health, Yale University School of Medicine
  • , Yong ZhuAffiliated withDepartment of Epidemiology and Public Health, Yale University School of Medicine Email author 
  • , Dionyssios KatsaroAffiliated withDepartment of Obstetrics and Gynecology, Gynecologic Oncology and Breast Cancer Unit, University of Turin

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Abstract

Mounting evidence suggests that neuronal PAS domain protein 2 (NPAS2) and other circadian genes are involved in tumorigenesis and tumor growth, possibly through their control of cancer-related biologic pathways. A missense polymorphism in NPAS2 (Ala394Thr) has been shown to be associated with risk of human tumors including breast cancer. The current study further examined the prognostic significance of NPAS2 in breast cancer by genotyping the Ala394Thr polymorphism and measuring NPAS2 expression. DNA extracted from 348 breast cancer tissue samples was analyzed for NPAS2 genotype using the TaqMan allelic discrimination assay. Of these, 287 also had total RNA available for use in real-time PCR assays to determine NPAS2 expression. NPAS2 genotypes and expression levels were analyzed for associations with prognostic outcomes, as well as correlations with clinical characteristics. A high level of NPAS2 expression was strongly associated with improved disease free survival (AHR = 0.43, 95% CI: 0.21–0.86, P trend = 0.022) and overall survival (AHR = 0.42, 95% CI: 0.19–0.96, P trend = 0.036). In addition, there was a borderline, but nonsignificant association between the NPAS2 genotype corresponding to Thr394Thr and disease free survival (AHR = 1.82, 95% CI: 0.96–3.46). The Ala/Ala, Ala/Thr, and Thr/Thr genotypes were also differentially distributed by tumor severity, as measured by TNM classification (χ 2 (6df, N = 344) = 14.96, P = 0.020). These findings provide the first evidence suggesting prognostic significance of the circadian gene NPAS2 in breast cancer.

Keywords

Circadian gene NPAS2 Breast caner Survival