The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer
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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.
KeywordsCircadian gene NPAS2 Breast caner Survival
This work was supported by the US National Institutes of Health (grant CA122676 and CA110937).
- 18.Tokunaga H, Takebayashi Y, Utsunomiya H, Akahira JI, Higashimoto M, Mashiko M, Ito K, Niikura H, Takenoshita SI, Yaegashi N (2008) Clinicopathological significance of circadian rhythm-related gene expression levels in patients with epithelial ovarian cancer. Acta Obstet Gynecol Scand:1–11Google Scholar
- 19.Sobin LH, Fleming ID (1997) TNM Classification of Malignant Tumors, fifth edition. Union Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer, 80:1803-1804Google Scholar
- 22.Mukaiyama Y, Uchida T, Sato E, Sasaki A, Sato Y, Igarashi J, Kurokawa H, Sagami I, Kitagawa T, Shimizu T (2006) Spectroscopic and DNA-binding characterization of the isolated heme-bound basic helix-loop-helix-PAS-A domain of neuronal PAS protein 2 (NPAS2), a transcription activator protein associated with circadian rhythms. FEBS J 273:2528–2539CrossRefPubMedGoogle Scholar
- 27.Garcia-Saenz JA, Martin M, Maestro M, Vidaurreta M, Veganzones S, Villalobos L, Rodriguez-Lajusticia L, Rafael S, Sanz-Casla MT, Casado A, Sastre J, Arroyo M, Diaz-Rubio E (2006) Circulating tumoral cells lack circadian-rhythm in hospitalized metastasic breast cancer patients. Clin Transl Oncol 8:826–829CrossRefPubMedGoogle Scholar