Three known non-synonymous polymorphisms (Ala394Thr, Ser471Leu and Pro690Ala) in the largest circadian gene, Neuronal PAS domain protein 2 (NPAS2), were genotyped in a breast cancer case-control study conducted in Connecticut, USA (431 cases and 476 controls). We found that women with the heterozygous Ala394Thr genotype were significantly associated with breast cancer risk compared to those with the common homozygous Ala394Ala (OR = 0.61, 0.46–0.81, P = 0.001). This is the first evidence demonstrating a role of the circadian gene NPAS2 in human breast cancer, suggesting that genetic variations in circadian genes might be a novel panel of biomarkers for breast cancer risk.
Circadian gene NPAS2 Breast cancer
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This study was supported by funds from Yale University. The work was also supported by the NIH grants CA62986, CA110937, CA108369, ES11659 and CA122676.
Davis S, Mirick DK, Stevens RG (2001) Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 93:1557–1562PubMedCrossRefGoogle Scholar
Schernhammer ES, Laden F, Speizer FE et al (2001) Rotating night shifts and risk of breast cancer in women participating in the nurses’ health study. J Natl Cancer Inst 93:1563–1568PubMedCrossRefGoogle Scholar
Lie JA, Roessink J, Kjaerheim K (2006) Breast cancer and night work among Norwegian nurses. Cancer Causes Control 17:39–44PubMedCrossRefGoogle Scholar
Stevens RG (2005) Circadian disruption and breast cancer: from melatonin to clock genes. Epidemiology 16:254–258PubMedCrossRefGoogle Scholar
Vitaterna MH, King DP, Chang AM et al (1994) Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264:719–725PubMedCrossRefGoogle Scholar
Bunger MK, Wilsbacher LD, Moran SM et al (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103:1009–1017PubMedCrossRefGoogle Scholar
Dudley CA, Erbel-Sieler C, Estill SJ et al (2003) Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301:379–383PubMedCrossRefGoogle Scholar
Zheng T, Holford TR, Mayne ST et al (2000) Risk of female breast cancer associated with serum polychlorinated biphenyls and 1,1-dichloro-2,2’-bis(p-chlorophenyl)ethylene. Cancer Epidemiol Biomarkers Prev 9:167–174PubMedGoogle Scholar
Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T (2005) Period3 Structural Variation: A circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev 14:268–270PubMedGoogle Scholar
Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50PubMedCrossRefGoogle Scholar
Johansson C, Willeit M, Smedh C et al (2003) Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference. Neuropsychopharmacology 28:734–739PubMedCrossRefGoogle Scholar
Lam RW, Levitan RD (2000) Pathophysiology of seasonal affective disorder: a review. J Psychiatry Neurosci 25:469–480PubMedGoogle Scholar
Zhu Y, Leaderer D, Guss C et al (2007) Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin’s lymphoma. Int J Cancer 120:432–435PubMedCrossRefGoogle Scholar
Walters JF, Hampton SM, Deanfield JE et al (2006) Circadian variation in endothelial function is attenuated in postmenopausal women. Maturitas 54:294–303PubMedCrossRefGoogle Scholar
Koyanagi S, Kuramoto Y, Nakagawa H et al (2003) A molecular mechanism regulating circadian expression of vascular endothelial growth factor in tumor cells. Cancer Res 63:7277–7283PubMedGoogle Scholar
Wood PA, Du-Quiton J, You S, Hrushesky WJ (2006) Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index. Mol Cancer Ther 5:2023–2033PubMedCrossRefGoogle Scholar
Hrushesky WJ, Bluming AZ, Gruber SA, Sothern RB (1989) Menstrual influence on surgical cure of breast cancer. Lancet 2:949–952PubMedCrossRefGoogle Scholar
Retsky M, Demicheli R, Hrushesky W (2001) Breast cancer screening for women aged 40–49 years: screening may not be the benign process usually thought. J Natl Cancer Inst 93:1572PubMedGoogle Scholar
Cartegni L, Chew SL, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 3:285–298PubMedCrossRefGoogle Scholar