ISSN 2415-3060 (print), ISSN 2522-4972 (online)
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УЖМБС 2021, 6(6): 93–99
https://doi.org/10.26693/jmbs06.06.093
Clinical Medicine

Analysis of the Link between rs4977574 Single Nucleotide Polymorphism of the Long Non-Coding RNA ANRIL Gene and Prostate Cancer Development

Volkogon A. D., Harbuzova V. Yu., Ataman O. V.
Abstract

The purpose of the study was to investigate the possible association between ANRIL gene rs4977574-polymorphism and prostate cancer occurrence among men of the Ukrainian population. Materials and methods. A total of 250 males were enrolled in the study. Of these, the experimental group included 184 prostate cancer patients, and the control group included 66 men without a history of malignant tumors. Genotyping of the ANRIL rs4977574 locus was performed by real-time polymerase chain reaction. The reaction was performed on a Quant Studio 5 DX Real-Time instrument (Applied Biosystems, USA) in the presence of TaqMan assays (TaqMan®SNP Assay C_31720978_30). The genotyping results were statistically processed using the SPSS software package (version 17.0). Values of p less than 0.05 were considered as statistically significant. Results and discussion. ANRIL (Antisense Non-coding RNA in the INK4 Locus), also known as CDKN2B-AS1, is a long non-coding RNA (3.8-kb) transcribed from the short arm of the human chromosome 9 (p21.3). ANRIL transcripts promote their main molecular effects through interaction with proteins of Polycomb repressive complex 1 and Polycomb repressive complex 2. Ultimately, this leads to epigenetic cis-inactivation of the tumor growth suppressor genes located in the Chr9p21 region: CDKN2A/p16INK4A, CDKN2A/p14ARF, CDKN2B/p15INK4B. Recent experimental studies have demonstrated the involvement of ANRIL in the development of malignant tumors of different localization. At the same time, there is almost no information about the role of the gene polymorphisms of this RNA in the occurrence of prostate cancer. The possible link between ANRIL gene polymorphism and prostate cancer risk in the Ukrainian population is not fully understood. It was found that the control men and prostate cancer patients did not differ significantly in the frequency of rs4977574-genotypes (p = 0.886). No significant difference was found during the corresponding comparison separately among persons with normal weight, overweight, without, and with the habit of smoking (p >0.05). Analysis of the association of different rs4977574 genotypes of the ANRIL gene with the risk of prostate cancer using logistic regression also did not show a reliable relationship under different models of inheritance, both before and after adjustment for age, body mass index and smoking (p >0.05). Conclusion. Thus, for the first time, we performed an analysis of the relation between ANRIL gene polymorphism and the development of malignant tumors of the genitourinary system in the Ukrainian population. The results showed that the polymorphic locus rs4977574 is not associated with the risk of prostate cancer

Keywords: long non-coding RNA, ANRIL, gene polymorphism, prostate cancer

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References
  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(6):394-424. https://www.ncbi.nlm.nih.gov/pubmed/30207593. https://doi.org/10.3322/caac.21492
  2. Rawla P. Epidemiology of Prostate Cancer. World J Oncol. 2019;10(2):63-89. https://www.ncbi.nlm.nih.gov/pubmed/31068988. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6497009. doi:10.14740/wjon1191
  3. Gu F, Pfeiffer RM, Bhattacharjee S, et al. Common genetic variants in the 9p21 region and their associations with multiple tumours. Br J Cancer. 2013;108(6):1378-1386. https://www.ncbi.nlm.nih.gov/pubmed/23361049. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3619272. https://doi.org/10.1038/bjc.2013.7
  4. Barros ÉAF, Pontes-Junior J, Reis ST, Lima AER, Souza IC, Salgueiro JL, et al. Correlation between chromosome 9p21 locus deletion and prognosis in clinically localized prostate cancer. Int J Biol Markers. 2017;32(2):e248-e254. https://www.ncbi.nlm.nih.gov/pubmed/28058701. https://doi.org/10.5301/jbm.5000242
  5. Li WQ, Pfeiffer RM, Hyland PL, Shi J, Gu F, Wang Z, et al. Genetic polymorphisms in the 9p21 region associated with risk of multiple cancers. Carcinogenesis. 2014;35(12):2698-2705. https://www.ncbi.nlm.nih.gov/pubmed/25239644. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4247519. https://doi.org/10.1093/carcin/bgu203
  6. Holdt LM, Teupser D. Long Noncoding RNA ANRIL: Lnc-ing Genetic Variation at the Chromosome 9p21 Locus to Molecular Mechanisms of Atherosclerosis. Front Cardiovasc Med. 2018;5:145. https://www.ncbi.nlm.nih.gov/pubmed/30460243. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6232298. https://doi.org/10.3389/fcvm.2018.00145
  7. Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell. 2010;38(5):662-674. https://www.ncbi.nlm.nih.gov/pubmed/20541999. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2886305. https://doi.org/10.1016/j.molcel.2010.03.021
  8. Zhao B, Lu YL, Yang Y, Hu LB, Bai Y, Li RQ, et al. Overexpression of lncRNA ANRIL promoted the proliferation and migration of prostate cancer cells via regulating let-7a/TGF-β1/ Smad signaling pathway. Cancer Biomark. 2018;21(3):613-620. https://www.ncbi.nlm.nih.gov/pubmed/29278879. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5859458. https://doi.org/10.3233/CBM-170683
  9. Congrains A, Kamide K, Ohishi M, Rakugi H. ANRIL: molecular mechanisms and implications in human health. Int J Mol Sci. 2013;14(1):1278-1292. https://www.ncbi.nlm.nih.gov/pubmed/23306151. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3565320. https://doi.org/10.3390/ijms14011278
  10. Kong Y, Hsieh CH, Alonso LC. ANRIL: A lncRNA at the CDKN2A/B Locus With Roles in Cancer and Metabolic Disease. Front Endocrinol (Lausanne). 2018;9:405. https://www.ncbi.nlm.nih.gov/pubmed/30087655. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6066557. https://doi.org/10.3389/fendo.2018.00405
  11. Khorshidi H, Taheri M, Noroozi R, Sarrafzadeh S, Sayad A, Ghafouri-Fard S. ANRIL Genetic Variants in Iranian Breast Cancer Patients. Cell J. 2017;19(Suppl 1):72-78. https://doi.org/10.22074/cellj.2017.4496
  12. Gong WJ, Yin J, Li XP, Fang C, Xiao D, Zhang W, et al. Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response. Tumour Biol. 2016;37(6):8349-8358. https://www.ncbi.nlm.nih.gov/pubmed/26729200. https://doi.org/10.1007/s13277-015-4497-5
  13. Poi M, Li J, Sborov D, VanGundy Z, Cho Y, Lamprecht M, et al. Polymorphism in ANRIL is associated with relapse in patients with multiple myeloma after autologous stem cell transplant. Mol Carcinog. 2017;56(7):1722-1732. https://www.ncbi.nlm.nih.gov/pubmed/28150872. https://doi.org/10.1002/mc.22626
  14. Xu B, Fang Z, He S, Wang J, Yang X. ANRIL polymorphism rs4977574 is associated with increased risk of coronary artery disease in Asian populations: A meta-analysis of 12,005 subjects. Medicine (Baltimore). 2018;97(39):e12641. https://www.ncbi.nlm.nih.gov/pubmed/30278588. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6181537. https://doi.org/10.1097/MD.000000000001264
  15. Hindy G, Ericson U, Hamrefors V, Drake I, Wirfält E, Melander O, et al. The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease: a population based cohort study. BMC Med Genet. 2014;15:1220. https://www.ncbi.nlm.nih.gov/pubmed/25551366. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4331503. https://doi.org/10.1186/s12881-014-0138-x
  16. Nelson CP, Goel A, Butterworth AS, Kanoni S, Webb TR, Marouli E, et al. Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nat Genet. 2017;49(9):1385-1391. https://www.ncbi.nlm.nih.gov/pubmed/28714975. https://doi.org/10.1038/ng.3913
  17. Wang Q, Zhao J, Chang H, Liu X, Zhu R. Association between lncRNA ANRIL genetic variants with the susceptibility to ischemic stroke: From a case-control study to meta-analysis. Medicine (Baltimore). 2021;100(11):e25113. https://www.ncbi.nlm.nih.gov/pubmed/33725991. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7982178. https://doi.org/10.1097/MD.0000000000025113
  18. Taheri M, Pouresmaeili F, Omrani MD, Habibi M, Sarrafzadeh S, Noroozi R et al. Association of ANRIL gene polymorphisms with prostate cancer and benign prostatic hyperplasia in an Iranian population. Biomark Med. 2017;11(5):413-422. https://www.ncbi.nlm.nih.gov/pubmed/28621612. https://doi.org/10.2217/bmm-2016-0378
  19. Tritto V, Ferrari L, Esposito S, Zuccotti P, Bianchessi D, Natacci F. Non-Coding RNA and Tumor Development in Neurofibromatosis Type 1: ANRIL Rs2151280 Is Associated with Optic Glioma Development and a Mild Phenotype in Neurofibromatosis Type 1 Patients. Genes (Basel). 2019;10(11): E892. https://www.ncbi.nlm.nih.gov/pubmed/31694342. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6895873. https://doi.org/10.3390/genes10110892
  20. Yuan W, Zhang W, Zhang W, Ruan ZB, Zhu L, Liu Y, et al. New findings in the roles of Cyclin-dependent Kinase inhibitors 2B Antisense RNA 1 (CDKN2B-AS1) rs1333049 G/C and rs4977574 A/G variants on the risk to coronary heart disease. Bioengineered. 2020;11(1):1084-1098. https://www.ncbi.nlm.nih.gov/pubmed/33054494. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8291866. https://doi.org/10.1080/2020.1827892
  21. Kunnas T, Piesanen J, Nikkari ST. Association of a Chromosome Locus 9p21.3 CDKN2B-AS1 Variant rs4977574 with Hypertension: The TAMRISK Study. Genet Test Mol Biomarkers. 2018;22(5):327-330. https://www.ncbi.nlm.nih.gov/pubmed/29791233. https://doi.org/10.1089/gtmb.2017.0249
  22. Sarkar D, Oghabian A, Bodiyabadu PK, Joseph WR, Leung EY, Finlay GJ, et al. Multiple Isoforms of ANRIL in Melanoma Cells: Structural Complexity Suggests Variations in Processing Int J Mol Sci. 2017;18(7):1378. https://www.ncbi.nlm.nih.gov/pubmed/28653984. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5535871. https://doi.org/10.3390/ijms18071378