PER3 polymorphisms and their association with prostate cancer risk in Japanese men


Prostate cancer


Introduction: Prostate cancer (PCa) is one of the most common cancers affecting men globally. Although PER3 has been suggested as a risk factor for cancer development, there are few reports elucidating the relationship between PER3 and PCa. We investigated the association between PER3 polymorphisms (rs2640908 and VNTR) and susceptibility to PCa in the Japanese population.

Methods: Eighty three patients with PCa and 122 controls participated in this study. We analyzed rs2640908 and VNTR polymorphisms by using PCR–Restriction Fragment Length Polymorphism (PCR–RFLP).

Results: Compared to the C/C genotype with the rs2640908 polymorphism, the T/T (OR: 0.35, 95% CI: 0.15–0.81, P = 0.02) and C/T + T/T (OR: 0.46, 95% CI: 0.24–0.88, P = 0.02) genotypes had a significantly lower risk of PCa. TT (OR: 0.29, 95% CI: 0.10–0.77, P = 0.02) and CT + TT (OR: 0.47, 95% CI: 0.23–0.97, P = 0.04) also had significant protection against PCa in the smoker group. Significantly, we observed an association between smoking and rs2640908 polymorphism in this study. However, no association between the VNTR polymorphisms and PCa was detected.

Conclusions: Our results suggest that PER3 rs2640908 polymorphisms influence an individual’s susceptibility to PCa.


[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68: 394–424. doi:10.3322/caac.21492
[2] 3. Center for Cancer Control and Information Services NCC. Projected Cancer Statistics. 2015. Available:
[3] International Agency for Research Center. Global Cancer Observatory. 2018. Available:
[4] Verma M, Patel P, Verma M. Biomarkers in prostate cancer epidemiology. Cancers (Basel). 2011;3: 3773–3798. doi:10.3390/cancers3043773
[5] Wendeu-Foyet MG, Menegaux F. Circadian Disruption and Prostate Cancer Risk: An Updated Review of Epidemiological Evidences. Cancer Epidemiol Biomarkers Prev. 2017;26: 985–991. doi:10.1158/1055-9965.EPI-16-1030
[6] Straif K, Baan R, Grosse Y, Secretan B, Ghissassi F El, Bouvard V, Altieri A. Carcinogenicity of shift-work , painting , and fire-fighting. Lancet Oncol. 2007;8: 1065–1066.
[7] Dibner C, Schibler U, Albrecht U. The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks. Annual Review of Physiology. 2010. doi:10.1146/annurev-physiol-021909-135821
[8] Lowrey PL, Takahashi JS. MAMMALIAN CIRCADIAN BIOLOGY: Elucidating Genome-Wide Levels of Temporal Organization. Annu Rev Genomics Hum Genet. 2004;5: 407–441. doi:10.1146/annurev.genom.5.061903.175925
[9] Kondratov R V., Chernov M V., Kondratova AA, Gorbacheva VY, Gudkov A V., Antoch MP. BMAL1-dependent circadian oscillation of nuclear CLOCK: Posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev. 2003. doi:10.1101/gad.1099503
[10] DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci. 2007;10: 543–5. doi:10.1038/nn1884
[11] Asher G, Schibler U. A CLOCK-less clock. Trends Cell Biol. 2006;16: 547–9. doi:10.1016/j.tcb.2006.09.005
[12] Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 1999;98: 193–205. doi:10.1016/S0092-8674(00)81014-4
[13] Dunlap JC. Molecular bases for circadian clocks. Cell. 1999;96: 271–290. doi:10.1016/S0092-8674(00)80566-8
[14] Wang X, Yan D, Teng M, Fan J, Zhou C, Li D, Qiu G, Sun X, Li T, Xing T, Tang H, Peng X, Peng Z. Reduced expression of PER3 is associated with incidence and development of colon cancer. Ann Surg Oncol. 2012;19: 3081–8. doi:10.1245/s10434-012-2279-5
[15] Yang MY, Chang JG, Lin PM, Tang KP, Chen YH, Lin HYH, Liu TC, Hsiao HH, Liu YC, Lin SF. Downregulation of circadian clock genes in chronic myeloid leukemia: Alternative methylation pattern of hPER3. Cancer Sci. 2006;97: 1298–1307. doi:10.1111/j.1349-7006.2006.00331.x
[16] Oshima T, Takenoshita S, Akaike M, Kunisaki C, Fujii S, Nozaki A, Numata K, Shiozawa M, Rino Y, Tanaka K, Masuda M, Imada T. Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep. 2011;25: 1439–1446. doi:10.3892/or.2011.1207
[17] Zhu Y, Stevens RG, Hoffman AE, FitzGerald LM, Kwon EM, Ostrander EA, Davis S, Zheng T, Stanford JL. Testing the circadian gene hypothesis in prostate cancer: A population-based case-control study. Cancer Res. 2009;69: 9315–9322. doi:10.1158/0008-5472.CAN-09-0648
[18] Alexander M, Burch JB, Steck SE, Chen CF, Hurley TG, Cavicchia P, Ray M, Shivappa N, Gues J, Zhang H, Youngstedt SD, Crek KE, Lloyd S, Yang X, Hébert JR. Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation. Oncol Rep. 2015;33: 935–941. doi:10.3892/or.2014.3667
[19] Zienolddiny S, Haugen A, Lie J-AS, Kjuus H, Anmarkrud KH, Kjaerheim K. Analysis of polymorphisms in the circadian-related genes and breast cancer risk in Norwegian nurses working night shifts. Breast Cancer Res. 2013;15: R53. doi:10.1186/bcr3445
[20] Qu F, Qiao Q, Wang N, Ji G, Zhao H, He L, Wang H, Bao G. Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients. Sci Rep. 2016;6: 22424. doi:10.1038/srep22424
[21] Zhao B, Lu J, Yin J, Liu H, Guo X, Yang Y, Ge N, Zhu Y, Zhang H, Xing J. A functional polymorphism in PER3 gene is associated with prognosis in hepatocellular carcinoma. Liver Int. 2012;32: 1451–1459. doi:10.1111/j.1478-3231.2012.02849.x
[22] Holipah, Hinoura T, Kozaka N, Kuroda Y. The correlation between PER3 rs2640908 polymorphism and colorectal Cancer in the Japanese population. Appl Cancer Res. 2019;39: 4–9. doi:10.1186/s41241-019-0072-5
[23] Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T. Period3 structural variation: a circadian biomarker associated with breast cancer in young women. Cancer Epidemiol Biomarkers Prev. 2005. doi:14/1/268 [pii]
[24] Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, Arendt J, Von Schantz M. A length polymorphism in the circadian clock gene Per3 is linked to delayed sleep phase syndrome and extreme diurnal preference. Sleep. 2003;26: 413–415. doi:10.1093/sleep/26.4.413
[25] Ebisawa T, Uchiyama M, Kajimura N, Mishima K, Kamei Y, Katoh M, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001;2: 342–346. doi:10.1093/embo-reports/kve070
[26] Guess J, Burch JB, Ogoussan K, Armstead CA, Zhang H, Wagner S, Hebert JR, Wood P, Youngstedt SD, Hofseth LJ, Singh UP, Xie D, Hrushesky WLM. Circadian disruption, Per3, and human cytokine secretion. Integr Cancer Ther. 2009;8: 329–336. doi:10.1177/1534735409352029
[27] Huang XL, Fu CJ, Bu RF. Role of circadian clocks in the development and therapeutics of cancer. J Int Med Res. 2011;39: 2061–2066. doi:10.1177/147323001103900601
[28] Reszka E, Wieczorek E, Przybek M, Jabłońska E, Kałużny P, Bukowska-Damska A, Zienolddiny S, Pepłońska B. Circadian gene methylation in rotating-shift nurses: a cross-sectional study. Chronobiol Int. 2018;35: 111–121. doi:10.1080/07420528.2017.1388252
[29] Masri S, Zocchi L, Katada S, Mora E, Sassone-Corsi P. The circadian clock transcriptional complex: Metabolic feedback intersects with epigenetic control. Ann N Y Acad Sci. 2012;1264: 103–109. doi:10.1111/j.1749-6632.2012.06649.x
[30] Fu L, Lee CC. The circadian clock: pacemaker and tumour suppressor. Nat Rev Cancer. 2003;3: 350–361. doi:10.1038/nrc1072
[31] Reddy AB, Wong GKY, O’Neill J, Maywood ES, Hastings MH. Circadian clocks: Neural and peripheral pacemakers that impact upon the cell division cycle. Mutat Res - Fundam Mol Mech Mutagen. 2005;574: 76–91. doi:10.1016/j.mrfmmm.2005.01.024
[32] Kondratov R V., Gorbacheva VY, Antoch MP. The Role of Mammalian Circadian Proteins in Normal Physiology and Genotoxic Stress Responses. Curr Top Dev Biol. 2007;78: 173–216. doi:10.1016/S0070-2153(06)78005-X
[33] Im JS, Jung BH, Kim SE, Lee KH, Lee JK. Per3, a circadian gene, is required for Chk2 activation in human cells. FEBS Lett. 2010;584: 4731–4734. doi:10.1016/j.febslet.2010.11.003
[34] Climent J, Perez-Losada J, Quigley DA, Kim IJ, Delrosario R, Jen KY, Bosch A, Lluch A, Mao JH, Balmain A. Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer. J Clin Oncol. 2010;28: 3770–3778. doi:10.1200/JCO.2009.27.0215
[35] Tan W, Wang W, Ma Q. Physiological and pathological function of serine/arginine-rich splicing factor 4 and related diseases. Biomed Res Int. 2018;3819719. doi:10.1155/2018/3819719
[36] Yamaguchi S, Shinmura K, Saitoh T, Takenoshita S, Kuwano H, Yokota J. A single nucleotide polymorphism at the splice donor site of the human MYH base excision repair gene results in reduced translation efficiency of its transcripts. Genes to Cells. 2002;7: 461–474. doi:10.1046/j.1365-2443.2002.00532.x
[37] Chu LW, Zhu Y, Yu K, Zheng T, Yu H, Zhang Y, Sesterhenn I, Chokkalingam AP, Danforth KN, Shen MC, Stanczyk FZ, Gao YT, Hsing AW. Variants in circadian genes and prostate cancer risk: A population-based study in China. Prostate Cancer Prostatic Dis. 2008;11: 342–348. doi:10.1038/sj.pcan.4501024
[38] Geng P, Ou J, Li J, Wang N, Xie G, Sa R, Liu C, Xiang L, Liang H. Genetic association between PER3 genetic polymorphisms and cancer susceptibility. Med (United States). 2015;94: 1–6. doi:10.1097/MD.0000000000000568
[39] Wirth MD, Burch JB, Hébert JR, Kowtal P, Mehrotra-Kapoor A, Steck SE, Hurley TG, Gupta PC, Pednekar MS, Youngstedt SD, Zhang H, Sarin R. Case-control study of breast cancer in India: Role of PERIOD3 clock gene length polymorphism and chronotype. Cancer Invest. 2014;32: 321–329. doi:10.3109/07357907.2014.919305
[40] Ebel GS, Gerstmayer B, Kuhl P, Borlak J, Meurrens K, Müller T. The kinetics of transcriptomic changes induced by cigarette smoke in rat lungs reveals a specific program of defense, inflammation, and circadian clock gene expression. Toxicol Sci. 2006;93: 422–431. doi:10.1093/toxsci/kfl071
[41] Rutter J, Reick M, Wu LC, McKnight SL. Regulation of crock and NPAS2 DNA binding by the redox state of NAD cofactors. Science (80- ). 2001;293: 510–4. doi:10.1126/science.1060698
[42] Jin X, Wu X, Roth JA, Amos CI, King TM, Branch C, Honn SE, Spitz MR. Higher lung cancer risk for younger African-americans with the pro/pro p53 genotype. Carcinogenesis. 1995;16: 2205–2208. doi:10.1093/carcin/16.9.2205
[43] Kuroda Y, Tsukino H, Nakao H, Imai H, Katoh T. P53 Codon 72 Polymorphism and Urothelial Cancer Risk. Cancer Lett. 2003;189: 77–83. doi:10.1016/S0304-3835(02)00518-9
[44] Cerliani MB, Pavicic W, Gili JA, Klein G, Saba S, Richard S. Cigarette smoking, dietary habits and genetic polymorphisms in GSTT1 , GSTM1 and CYP1A1 metabolic genes: A case-control study in oncohematological diseases. World J Clin Oncol. 2016;7: 395–405. doi:10.5306/wjco.v7.i5.395