Abstract
Uterine leiomyoma (UL) is a monoclonal tumor which arises from uninhibited proliferation of a single myometrial cell; therefore, the imbalance in cell cycle regulation could be a key event in its development. In the present study, we aimed to assess the association of p21 gene polymorphisms and UL. Genomic DNA was extracted from blood samples of 154 women with UL and 197 age-, BMI-, and ethnically matched controls. p21 C98A (rs1801270) and C70T (rs1059234) polymorphism genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The CA genotype of p21 C98A polymorphism was significantly higher in UL women (28 %) compared to the controls (18 %), and the UL risk was 1.8-fold greater in women with CA genotype compared to CC genotype before and after adjusting for age, BMI, and ethnicity (OR, 1.8 [95 % CI, 1.1 to 3]; P = 0.02). There was no association between the AA genotype of p21 C98A polymorphism and UL. Moreover, the frequency of p21 98A allele was significantly higher in the UL women compared to controls (17 vs. 12 %, p = 0.04). The p21 C70T polymorphism did not correlate with UL before and after adjusting for age, BMI, and ethnicity. There was no difference in haplotype frequency of p21 C70T and C98A polymorphisms between UL patients and the controls. CA genotype of p21 C98A polymorphism may be a risk factor for UL susceptibility; however, p21 C70T polymorphism did not associate with UL.
Similar content being viewed by others
References
Laughlin SK, Stewart EA. Uterine leiomyomas: individualizing the approach to a heterogeneous condition. Obstet Gynecol. 2011;117(2 Pt 1):396–403. doi:10.1097/AOG.0b013e31820780e3.
Styer AK, Rueda BR. The epidemiology and genetics of uterine leiomyoma. Best Pract Res Clin Obstet Gynaecol. 2015. doi:10.1016/j.bpobgyn.2015.11.018.
Leppert PC, Catherino WH, Segars JH. A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays. Am J Obstet Gynecol. 2006;195(2):415–20. doi:10.1016/j.ajog.2005.12.059.
Hoffman PJ, Milliken DB, Gregg LC, Davis RR, Gregg JP. Molecular characterization of uterine fibroids and its implication for underlying mechanisms of pathogenesis. Fertil Steril. 2004;82(3):639–49. doi:10.1016/j.fertnstert.2004.01.047.
Falcone T, Walters MD. Hysterectomy for benign disease. Obstet Gynecol. 2008;111(3):753–67. doi:10.1097/AOG.0b013e318165f18c.
Fritz MA, Speroff L. Clinical gynecologic endocrinology and infertility. 8 th ed. Phyladelphia: Wolters Kluwer; 2011. p. 148.
Berek JS. Berek & Novak’s gynecology. 15 th ed. Phyladelphia: Lippincott Williams & Wilkins; 2012. p. 439.
Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril. 2007;87(4):725–36. doi:10.1016/j.fertnstert.2007.01.093.
Sabbah M, Courilleau D, Mester J, Redeuilh G. Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci U S A. 1999;96(20):11217–22.
Han SS, No JH, Jeon YT, Kim JW, Park NH, Song YS, et al. Association of cyclin D1 G870a polymorphism with uterine leiomyoma in women whose body mass index values are above 25 kg/m2. Hum Reprod. 2008;23(3):525–9. doi:10.1093/humrep/dem407.
Knappskog S, Lonning PE. MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk. Oncotarget. 2011;2(3):251–8.
Salimi S, Hajizadeh A, Khodamian M, Pejman A, Fazeli K, Yaghmaei M. Age-dependent association of MDM2 promoter polymorphisms and uterine leiomyoma in South-East Iran: a preliminary report. J Obstet Gynaecol Res. 2015;41(5):729–34. doi:10.1111/jog.12625.
Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31. doi:10.1016/S0092-8674(00)81871-1.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75(4):817–25. doi:10.1016/0092-8674(93)90500-P.
el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res. 1994;54(5):1169–74.
Chedid M, Michieli P, Lengel C, Huppi K, Givol D. A single nucleotide substitution at codon 31 (Ser/Arg) defines a polymorphism in a highly conserved region of the p53-inducible gene WAF1/CIP1. Oncogene. 1994;9(10):3021–4.
Li G, Liu Z, Sturgis EM, Shi Q, Chamberlain RM, Spitz MR, et al. Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis. 2005;26(9):1596–602. doi:10.1093/carcin/bgi105.
Amara FM, Chen FY, Wright JA. Defining a novel cis element in the 3'-untranslated region of mammalian ribonucleotide reductase component R2 mRNA: role in transforming growth factor-beta 1 induced mRNA stabilization. Nucleic Acids Res. 1995;23(9):1461–7.
Fan H, Villegas C, Huang A, Wright JA. Suppression of malignancy by the 3' untranslated regions of ribonucleotide reductase R1 and R2 messenger RNAs. Cancer Res. 1996;56(19):4366–9.
Salimi S, Hajizadeh A, Khodamian M, Pejman A, Fazeli K, Yaghmaei M. Age-dependent association of MDM2 promoter polymorphisms and uterine leiomyoma in South-East Iran: a preliminary report. J Obstet Gynaecol Res. 2014. doi:10.1111/jog.12625.
Hsieh YY, Wang JP, Lin CS. Four novel single nucleotide polymorphisms within the promoter region of p53 gene and their associations with uterine leiomyoma. Mol Reprod Dev. 2007;74(7):815–20. doi:10.1002/mrd.20464.
Huang SP, Wu WJ, Chang WS, Wu MT, Chen YY, Chen YJ, et al. p53 codon 72 and p21 codon 31 polymorphisms in prostate cancer. Cancer Epidemiol Biomark Prev. 2004;13(12):2217–24.
Facher EA, Becich MJ, Deka A, Law JC. Association between human cancer and two polymorphisms occurring together in the p21Waf1/Cip1 cyclin-dependent kinase inhibitor gene. Cancer. 1997;79(12):2424–9. doi:10.1002/(SICI)1097-0142(19970615)79:12<2424::AID-CNCR19>3.0.CO;2-T.
Kumazaki K, Nakayama M, Suehara N, Wada Y. Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathologic conditions. Hum Pathol. 2002;33(11):1069–77.
Waga S, Li R, Stillman B. p53-induced p21 controls DNA replication. Leukemia. 1997;11(Suppl 3):321–3.
Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis. Mol Cancer Ther. 2002;1(8):639–49.
Elbendary AA, Cirisano FD, Evans Jr AC, Davis PL, Iglehart JD, Marks JR, et al. Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells. Clin Cancer Res. 1996;2(9):1571–5.
el-Deiry WS, Tokino T, Waldman T, Oliner JD, Velculescu VE, Burrell M, et al. Topological control of p21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 1995;55(13):2910–9.
Lora V, Grings AO, Capp E, von Eye CH, Brum IS. Gene and protein expression of progesterone receptor isoforms A and B, p53 and p21 in myometrium and uterine leiomyoma. Arch Gynecol Obstet. 2012;286(1):119–24. doi:10.1007/s00404-012-2245-2.
Palazzo JP, Mercer WE, Kovatich AJ, McHugh M. Immunohistochemical localization of p21(WAF1/CIP1) in normal, hyperplastic, and neoplastic uterine tissues. Hum Pathol. 1997;28(1):60–6. doi:10.1016/S0046-8177(97)90280-X.
Hsieh YY, Chang CC, Hsu CW, Lin CS. Gene transfections with p53 and p21 inhibit cell proliferation, collagen type I, leukemia inhibitory factor, and tumor necrosis factor-alpha expression in leiomyoma cells. Fertil Steril. 2004;81(6):1665–70. doi:10.1016/j.fertnstert.2004.02.062.
Hsieh YY, Chang CC, Bau DT, Tsai FJ, Tsai CH, Chen CP. The p21 codon 31*C- and DRD2 codon 313*T-related genotypes/alleles, but not XRCC1 codon 399, hOGG1 codon 326, and DRD1-48 polymorphisms, are correlated with the presence of leiomyoma. Fertil Steril. 2009;91(3):869–77. doi:10.1016/j.fertnstert.2007.07.1328.
Ma Y, Zhang Y, Lin L, Guo X, Wu Y, Wen W, et al. Quantitative assessment of the relationship between p21 Ser31Arg polymorphism and cervical cancer. Tumour Biol J Int Soc Oncodevelopmental Biol Med. 2013;34(6):3887–92. doi:10.1007/s13277-013-0976-8.
Harima Y, Sawada S, Nagata K, Sougawa M, Ostapenko V, Ohnishi T. Polymorphism of the WAF1 gene is related to susceptibility to cervical cancer in Japanese women. Int J Mol Med. 2001;7(3):261–4.
Roh JW, Kim BK, Lee CH, Kim J, Chung HH, Kim JW, et al. P53 codon 72 and p21 codon 31 polymorphisms and susceptibility to cervical adenocarcinoma in Korean women. Oncol Res. 2010;18(9):453–9.
Carvalho IN, Reis AH, Cabello PH, Vargas FR. Polymorphisms of CDKN1A gene and risk of retinoblastoma. Carcinogenesis. 2013;34(12):2774–7. doi:10.1093/carcin/bgt308.
Wang N, Wang S, Zhang Q, Lu Y, Wei H, Li W, et al. Association of p21 SNPs and risk of cervical cancer among Chinese women. BMC Cancer. 2012;12:589. doi:10.1186/1471-2407-12-589.
Sivonova MK, Vilckova M, Kliment J, Mahmood S, Jurecekova J, Dusenkova S, et al. Association of and polymorphisms with prostate cancer. Biomed Rep. 2015;3(5):707–14. doi:10.3892/br.2015.496.
Huang YS, Fan QQ, Li C, Nie M, Quan HY, Wang L. Quantitative assessment the relationship between p21 rs1059234 polymorphism and cancer risk. Asian Pac J Cancer Prev APJCP. 2015;16(10):4435–8.
Acknowledgment
This article was extracted from the MS thesis (registered number 2161) at Zahedan University of Medical Sciences. The authors would like to thank the Deputy of Research Affairs at the University for funding this project.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All participants were Iranian and gave their informed consent before participating in the study. The protocol of this study was approved by the Ethics Committee of Zahedan University of Medical Sciences and conducted in accordance with the Declaration of Helsiniki.
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Salimi, S., Hajizadeh, A., Yaghmaei, M. et al. The effects of p21 gene C98A polymorphism on development of uterine leiomyoma in southeast Iranian women. Tumor Biol. 37, 12497–12502 (2016). https://doi.org/10.1007/s13277-016-5078-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-016-5078-y