The Association of rs1042522 and rs3088440 Polymorphisms with CA125, IFN-γ, and IL-10 Levels in Cervical Cancer and Genital Warts Patients
Keywords:
interleukin-10, genetic polymorphism, papillomavirus infections, p53, uterine cervical neoplasmsAbstract
Introduction: Variants in tumor suppressor genes may affect susceptibility to HPV-related diseases and alter immune responses by modifying cytokine production. Thus, in the current study, we sought to examine how rs1042522 (TP53 codon 72) and rs3088440 (INK4a 540 C>T) variants correlate with serum CA125, IFN-γ, and IL-10 levels in Iraqi women with cervical cancer, genital warts, or no disease.
Methods: We enrolled 106 participants from four Iraqi hospitals (October 2024-January 2025): 26 with cervical cancer, 30 with genital warts, and 50 healthy individuals. Genetic variants were identified through PCR-RFLP, and ELISA was used to measure CA125, IFN-γ, and IL-10 in serum. We applied Chi-square tests for genotype frequencies and Kruskal-Wallis followed by Mann-Whitney U tests for biomarker analysis.
Results: For rs1042522, controls had higher GG genotype frequency (46.0%) than genital warts patients (23.3%; P=0.03), whereas genital warts patients showed increased CC genotype (43.3%). Among genital warts patients, IL-10 concentrations varied by rs1042522 genotype (P=0.025): CC carriers had elevated levels (0.76 pg/mL) versus GG carriers (0.60 pg/mL; P=0.006). The rs3088440 variant showed no meaningful associations with disease or biomarkers.
Conclusion: Our findings link rs1042522 to genital warts risk and IL-10 regulation in affected patients, indicating a genetic basis for immune responses in HPV-associated conditions. This variant may serve as a useful marker for identifying at-risk individuals.
References
Wu J, Jin Q, Zhang Y, Ji Y, Li J, Liu X, et al. Global burden of cervical cancer: current estimates, temporal trend and future projections based on the GLOBOCAN 2022. J Natl Cancer Cent [Internet]. 2025 Jun 29;5(3):322–9. Available from: https://cytojournal.com/cancer-cervix-epidemiology-and-disease-burden/
Bosch FX, Manos MM, Muñoz N, Sherman M, Jansen AM, Peto J, et al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J Natl Cancer Inst [Internet]. 1995 Jun 7;87(11):796–802. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7791229
Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine [Internet]. 2012 Nov;30:F12–23. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0264410X12010808
Seoud M. Burden of human papillomavirus-related cervical disease in the extended middle East and north Africa-a comprehensive literature review. J Low Genit Tract Dis [Internet]. 2012 Apr;16(2):106–20. Available from: https://journals.lww.com/00128360-201204000-00006
Obeid DA, Almatrrouk SA, Alfageeh MB, Al-Ahdal MNA, Alhamlan FS. Human papillomavirus epidemiology in populations with normal or abnormal cervical cytology or cervical cancer in the Middle East and North Africa: A systematic review and meta-analysis. J Infect Public Health [Internet]. 2020 Sep;13(9):1304–13. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1876034120305220
Alsbeih G. HPV infection in cervical and other cancers in Saudi Arabia: Implication for prevention and vaccination. Front Oncol [Internet]. 2014 Mar 31;4. Available from: http://journal.frontiersin.org/article/10.3389/fonc.2014.00065/abstract
Song SH, Lee JK, Lee NW, Saw HS, Kang JS, Lee KW. Interferon-γ (IFN-γ): A possible prognostic marker for clearance of high-risk human papillomavirus (HPV). Gynecol Oncol [Internet]. 2008 Mar;108(3):543–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0090825807009055
Tartour E, Gey A, Fridman WH, Sastre-Garau X, Lombard Surin I, Mosseri V. Prognostic value of intratumoral interferon gamma messenger RNA expression in invasive cervical carcinomas. JNCI J Natl Cancer Inst [Internet]. 1998 Feb 18;90(4):287–94. Available from: https://academic.oup.com/jnci/article-lookup/doi/10.1093/jnci/90.4.287
Bhairavabhotla RK, Verm V, Tongaonkar H, Shastri S, Dinshaw K, Chiplunkar S. Role of IL-10 in immune suppression in cervical cancer. Indian J Biochem Biophys [Internet]. 2007 Oct;44(5):350–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18341210
de Gruijl T., Bontkes H., van den Muysenberg AJ., van Oostveen J., Stukart M., Verheijen RH., et al. Differences in cytokine mRNA profiles between premalignant and malignant lesions of the uterine cervix. Eur J Cancer [Internet]. 1999 Mar;35(3):490–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0959804998003712
Wang Y, Liu XH, Li YH, Li O. The paradox of IL-10-mediated modulation in cervical cancer. Biomed reports [Internet]. 2013 May;1(3):347–51. Available from: https://www.spandidos-publications.com/10.3892/br.2013.69
Torres-Poveda K. Role of IL-10 and TGF-β1 in local immunosuppression in HPV-associated cervical neoplasia. World J Clin Oncol [Internet]. 2014;5(4):753. Available from: http://www.wjgnet.com/2218-4333/full/v5/i4/753.htm
Li L, Ma Y, Liu S, Zhang J, Xu XY. Interleukin 10 promotes immune response by increasing the survival of activated CD8+ T cells in human papillomavirus 16-infected cervical cancer. Tumor Biol [Internet]. 2016 Dec 11;37(12):16093–101. Available from: http://link.springer.com/10.1007/s13277-016-5466-3
Díaz-Benítez CE, Navarro-Fuentes KR, Flores-Sosa JA, Juárez-Díaz J, Uribe-Salas FJ, Román-Basaure E, et al. CD3ζ expression and T cell proliferation are inhibited by TGF-beta1 and IL-10 in cervical cancer patients. J Clin Immunol [Internet]. 2009 Jul 4;29(4):532–44. Available from: http://link.springer.com/10.1007/s10875-009-9279-7
Bast RC, Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, et al. New tumor markers: CA125 and beyond. Int J Gynecol Cancer [Internet]. 2005 Nov;15:274–81. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1048891X24193176
Bulgakova O, Kussainova A, Bersimbaev R. The cell cycle regulatory gene polymorphisms TP53 (rs1042522) and MDM2 (rs2279744) in lung cancer: a meta-analysis. Vavilov J Genet Breed [Internet]. 2020 Dec 6;24(7):77–784. Available from: https://vavilov.elpub.ru/jour/article/view/2821
Elshazli RM, Toraih EA, Elgaml A, Kandil E, Fawzy MS. Genetic polymorphisms of TP53 (rs1042522) and MDM2 (rs2279744) and colorectal cancer risk: An updated meta-analysis based on 59 case-control studies. Gene [Internet]. 2020 Apr;734:144391. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0378111920300603
Cheng C, Lingyan W, Yi H, Cheng Z, Huadan Y, Xuting X, et al. Association between TLR2, MTR, MTRR, XPC, TP73, TP53 genetic polymorphisms and gastric cancer: A meta-analysis. Clin Res Hepatol Gastroenterol [Internet]. 2014 Jun;38(3):346–59. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2210740114000060
Kamiza AB, Kamiza S, Singini MG, Mathew CG. Association of TP53 rs1042522 with cervical cancer in the sub‐Saharan African population: a meta‐analysis. Trop Med Int Heal [Internet]. 2020 Jun 16;25(6):666–72. Available from: https://onlinelibrary.wiley.com/doi/10.1111/tmi.13397
Chansaenroj J, Theamboonlers A, Junyangdikul P, Swangvaree S, Karalak A, Chinchai T, et al. Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) genes in Thai cervical cancer patients with HPV 16 infection. Asian Pacific J Cancer Prev [Internet]. 2013 Jan 31;14(1):341–6. Available from: http://koreascience.or.kr/journal/view.jsp?kj=POCPA9&py=2013&vnc=v14n1&sp=341
Lin HY, Huang CH, Wu WJ, Chang LC, Lung FW. TP53 codon 72 gene polymorphism paradox in associated with various carcinoma incidences, invasiveness and chemotherapy responses. Int J Biomed Sci [Internet]. 2008 Dec 15;4(4):248–54. Available from: https://ijbs.org/User/ContentFullTextFrame.aspx?VolumeNO=4&StartPage=248
De Souza C, Madden J, Koestler DC, Minn D, Montoya DJ, Minn K, et al. Effect of the p53 P72R Polymorphism on Mutant TP53 Allele Selection in Human Cancer. J Natl Cancer Inst [Internet]. 2021 Sep 4;113(9):1246–57. Available from: http://www.ncbi.nlm.nih.gov/pubmed/33555293
Jalil AT. Association of HPV16 viral load in gene l2 with cancer stages and demographic characteristics in cervical cancer patients from Dhi-Qar Province, Iraq. J Grodno State Med Univ [Internet]. 2023 Jul;21(3):266–73. Available from: http://journal-grsmu.by/index.php/ojs/article/view/3053
Magnusson PK, Lichtenstein P, Gyllensten UB. Heritability of cervical tumours. Int J cancer [Internet]. 2000 Dec 1;88(5):698–701. Available from: https://onlinelibrary.wiley.com/doi/abs/10.2134/jeq1997.00472425002600010048x
Rosenthal AN, Ryan A, Al-Jehani RM, Storey A, Harwood CA, Jacobs IJ. p53 codon 72 polymorphism and risk of cervical cancer in UK. Lancet [Internet]. 1998 Sep;352(9131):871–2. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673698073577
Abba M. p53 codon 72 genotypes in HPV infection and cervical disease. Eur J Obstet Gynecol Reprod Biol [Internet]. 2003 Jul 1;109(1):63–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0301211502004748
Calhoun ES, McGovern RM, Janney CA, Cerhan JR, Iturria SJ, Smith DI, et al. Host genetic polymorphism analysis in cervical cancer. Clin Chem [Internet]. 2002 Aug 1;48(8):1218–24. Available from: https://academic.oup.com/clinchem/article/48/8/1218/5642204
Habbous S, Pang V, Eng L, Xu W, Kurtz G, Liu FF, et al. p53 Arg72Pro polymorphism, HPV status and initiation, progression, and development of cervical cancer: a systematic review and meta-analysis. Clin Cancer Res [Internet]. 2012 Dec 1;18(23):6407–15. Available from: https://aacrjournals.org/clincancerres/article/18/23/6407/283685/p53-Arg72Pro-Polymorphism-HPV-Status-and
Isakova J, Vinnikov D, Bukuev N, Talaibekova E, Adasheva N. ТР53 Codon 72 Polymorphism and Human Papilloma Virus-Associated Cervical Cancer in Kyrgyz Women. Asian Pacific J Cancer Prev [Internet]. 2019 Apr 1;20(4):1057–62. Available from: http://journal.waocp.org/article_85920.html
Koushik A, Ghosh A, Duarte-Franco E, Forest P, Voyer H, Matlashewski G, et al. The p53 codon 72 polymorphism and risk of high-grade cervical intraepithelial neoplasia. Cancer Detect Prev [Internet]. 2005 Jan;29(4):307–16. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0361090X05000851
Al-Janabi AM, Hussein A, Algenabi A, Alkhafaji SM. Association of TP53 [Arg72Pro] Gene Polymorphism and Breast Cancer Risk in Iraqi female patients. Int J Sci Res [Internet]. 2015;6(12):1128–38. Available from: https://www.ijsr.net/getabstract.php?paperid=SR20617012741
Zidi S, Gazouani E, Stayoussef M, Mezlini A, Ahmed SK, Yacoubi-Loueslati B, et al. IL-10 gene promoter and intron polymorphisms as genetic biomarkers of cervical cancer susceptibility among Tunisians. Cytokine [Internet]. 2015 Dec;76(2):343–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S104346661500215X
Singhal P, Kumar A, Bharadwaj S, Hussain S, Bharadwaj M. Association of IL-10 GTC haplotype with serum level and HPV infection in the development of cervical carcinoma. Tumor Biol [Internet]. 2015 Apr 21;36(4):2287–98. Available from: http://link.springer.com/10.1007/s13277-014-2836-6
Ni J, Ye Y, Teng F, Wu Q. Interleukin 10 Polymorphisms and Cervical Cancer Risk. Int J Gynecol Cancer [Internet]. 2013 Jan;23(1):126–33. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1048891X24018292
Bai CY, Shi XY, He J, Xue J, Feng Y. Association between IL-10 genetic variations and cervical cancer susceptibility in a Chinese population. Genet Mol Res [Internet]. 2016;15(3). Available from: http://www.funpecrp.com.br/gmr/year2016/vol15-3/pdf/gmr8116.pdf
Du GH, Wang JK, Richards JR, Wang JJ. Genetic polymorphisms in tumor necrosis factor alpha and interleukin-10 are associated with an increased risk of cervical cancer. Int Immunopharmacol [Internet]. 2019 Jan;66:154–61. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1567576918304302
