Molecular and genetic patterns of prostate cancer in young men
DOI: 10.32364/2587-6821-2025-9-4-5
Molecular and genetic patterns of prostate cancer in young men
I.V. Volodina, A.Yu. Pavlov, A.G. Dzidzaria, A.D. Tsibulskii
Russian Scientific Center of Roentgenology and Radiology, Moscow, Russian Federation
Background: prostate cancer (PC) is the second most prevalent malignancy among male patients. The oncogenesis of PC may be attributed to alterations in multiple regulatory systems, potentially related to the presence of various genetic polymorphisms.
Aim: to study the expression and activity of a number of specific genes in patients with PC aged less than 55 years, whose gene products, according to the literature, are implicated in carcinogenesis.
Materials and Methods: the study cohort included 45 male patients with PC aged 55 years or younger. All participants underwent molecular genetic analysis of buccal epithelial cells to identify polymorphisms associated with alterations in the expression, activity, or susceptibility of genes encoding several hormones, receptors, enzymes, and other proteins implicated in PC pathogenesis. The following target genes were investigated: AR, SHBG, SRD5A2, CYP19A1, ESR1α, ESR2β, COMT, PGR, FADS2, PPARG, CYP27B1, and VDR.
Results: normal susceptibility, activity, or expression was most frequently observed for the VDR (82.2%), PGR (71.1%), and PPARG (68.9%) genes. In contrast, normal susceptibility/activity/expression was less commonly detected for the COMT (28.9%), CYP19A1 (35.6%), and ESR1α (37.8%) genes. Decreased susceptibility/activity/expression was predominantly observed for CYP27B1 (100%), COMT (71.1%), and CYP19A1 (64.4%), and less commonly for VDR (17.8%), PGR (28.9%), and PPARG (31.1%). Increased susceptibility/activity/expression was more frequently detected for ESR1α (62.2%) and FADS2 (22.2%), and less frequently for ESR2β (2.2%). Intermediate susceptibility was observed only for ESR2β (2.2%) and FADS2 (44.4%). Normal CYP19A1 activity was more frequently found in patients with prostate-specific antigen (PSA) levels ≤8.6 ng/mL than in those with PSA ≥8.6 ng/mL: 50.0% and 21.7%, respectively (p=0.047). Patients with PSA levels ≥8.6 ng/mL were more likely to exhibit decreased CYP19A1 activity. Among patients with a Gleason score ≤6, normal ESR2β expression was detected in 71.4% of cases, whereas in patients with a Gleason score ≥7, normal ESR2β expression was found in 41.2% of cases (p=0.072). A similar trend was observed for the PPARG gene: normal activity was present in 78.6% and 52.9% of cases in these respective groups (p=0.072).
Conclusion: PC is a multifactorial disease arising from dysregulation of the body's regulatory systems. In patients with PC, polymorphisms contribute to alterations in gene expression associated with varying degrees of activity of receptors, enzymes, and other proteins involved in oncogenesis.
Keywords: prostate cancer, carcinogenesis, androgen receptors, gene polymorphisms.
For citation: Volodina I.V., Pavlov A.Yu., Dzidzaria A.G., Tsibulskii A.D. Molecular and genetic patterns of prostate cancer in young men. Russian Medical Inquiry. 2025;9(4):214–222 (in Russ.). DOI: 10.32364/2587-6821-2025-9-4-5
ABOUT THE AUTHORS:
Irina V. Volodina — postgraduate student at the Department of Urology with Oncology Beds and Shock Wave Lithotripsy Rooms, Russian Scientific Center of Roentgenology and Radiology; 86, Profsoyuznaya str., Moscow, 117997, Russian Federation; ORCID iD 0000-0002-3327-6025
Andrey Yu. Pavlov — Dr. Sc. (Med.), Professor, Deputy Director for Scientific and Therapeutic Work, Russian Scientific Center of Roentgenology and Radiology; 86, Profsoyuznaya str., Moscow, 117997, Russian Federation; ORCID iD 0000-0002-2905-7735
Alexander V. Dzidzaria — Dr. Sc. (Med.), Deputy Director of the Department of Urology with Oncology Beds and Shock Wave Lithotripsy Rooms, Russian Scientific Center of Roentgenology and Radiology; 86, Profsoyuznaya str., Moscow, 117997, Russian Federation; ORCID iD 0000-0001-5789-375X
Alexey D. Tsibulskii — Dr. Sc. (Med.), Senior Researcher at the Department of Urology with Oncology Beds and Shock Wave Lithotripsy Rooms, Russian Scientific Center of Roentgenology and Radiology; 86, Profsoyuznaya str., Moscow, 117997, Russian Federation; ORCID iD 0000-0002-1647-6180
Contact information: Irina V. Volodina, e-mail: 79102882190@yandex.ru
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.
There is no conflict of interest.
Received 06.02.2025.
Revised 03.03.2025.
Accepted 26.03.2025.
2. Leach D.A., Fernandes R.C., Bevan C.L. Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer. Endocr Oncol. 2022;2(1):R112–R131. DOI: 10.1530/EO-22-0065
3. Liu M., Shi H., Yan J. et al. Gene polymorphism-related differences in the outcomes of abiraterone for prostate cancer: a systematic overview. Am J Cancer Res. 2021;11(5):1873–1894. PMID: 34094659
4. Shiota M., Akamatsu S., Narita S. et al. Genetic Polymorphisms and Pharmacotherapy for Prostate Cancer. JMA J. 2021;4(2):99–111. DOI: 10.31662/jmaj.2021-0004
5. Gregga I., Pharoah P.D.P., Gayther S.A. et al. Predicted Proteome Association Studies of Breast, Prostate, Ovarian, and Endometrial Cancers Implicate Plasma Protein Regulation in Cancer Susceptibility. Cancer Epidemiol Biomarkers Prev. 2023;32(9):1198–1207. DOI: 10.1158/1055-9965.EPI-23-0309.
6. Takeuchi T., Hattori-Kato M., Okuno Y. et al. A Genome-Wide Association Study of Prostate Cancer Susceptibility Using Occupational and Environmental Factors as Confounding Factors. Cureus. 2024;16(1):e52926. DOI: 10.7759/cureus.52926
7. Hishida A., Nakatochi M., Tamura T. et al. Genome-wide association study of serum prostate-specific antigen levels based on 1000 Genomes imputed data in Japanese: the Japan Multi-Institutional Collaborative Cohort Study. Nagoya J Med Sci. 2021;83(1):183–194.DOI: 10.18999/nagjms.83.1.183
8. Price D.K., Chau C.H., Till C. et al. Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial. Cancer. 2016;122(15):2332–2340. DOI: 10.1002/cncr.30071
9. Patke R., Harris A.E., Woodcock C.L. et al. Epitranscriptomic mechanisms of androgen signalling and prostate cancer. Neoplasia. 2024;56:101032. DOI: 10.1016/j.neo.2024.101032
10. Stanbrough M., Leav I., Kwan P.W. et al. Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci U S A. 2001;98(19):10823–10828. DOI: 10.1073/pnas.191235898
11. Han G., Buchanan G., Ittmann M. et al. Mutation of the androgen receptor causes oncogenic transformation of the prostate. Proc Natl Acad Sci U S A. 2005;102(4):1151–1156. DOI: 10.1073/pnas.0408925102
12. Wen S., Niu Y., Lee S.O. et al. Androgen receptor (AR) positive vs negative roles in prostate cancer cell deaths including apoptosis, anoikis, entosis, necrosis and autophagic cell death. Cancer Treat Rev. 2014;40(1):31–40. DOI: 10.1016/j.ctrv.2013.07.008
13. Song W., Khera M. Physiological normal levels of androgen inhibit proliferation of prostate cancer cells in vitro. Asian J Androl. 2014;16(6):864–868. DOI: 10.4103/1008-682X.129132
14. Mukherjee A.G., V G A. Sex hormone-binding globulin and its critical role in prostate cancer: A comprehensive review. J Steroid Biochem Mol Biol. 2025;245:106606. DOI: 10.1016/j.jsbmb.2024.106606
15. Wan B., Lu L., Lv C. Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone-binding globulin on prostate cancer. Andrology. 2023;11(6):1023–1030. DOI: 10.1111/andr.13358
16. Bamodu O.A., Tzou K.-Y., Lin C.-D. et al. Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer. Cancers (Basel). 2021;13(14):3478. DOI: 10.3390/cancers13143478
17. Kosaka T., Miyajima A., Nagata H. et al. Human castration resistant prostate cancer rather prefer to decreased 5α-reductase activity. Sci Rep. 2013;3:1268. DOI: 10.1038/srep01268
18. Meng J., Guan Y., Wang B. et al. Risk subtyping and prognostic assessment of prostate cancer based on consensus genes. Commun Biol. 2022;5(1):233. DOI: 10.1038/s42003-022-03164-8
19. Aggarwal S., Singh M., Kumar A. et al. SRD5A2 gene expression inhibits cell migration and invasion in prostate cancer cell line via F-actin reorganization. Mol Cell Biochem. 2015;408(1–2):15–23. DOI: 10.1007/s11010-015-2478-z
20. Mokhosoev I.M., Astakhov D.V., Terentiev A.A. et al. Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review. Cells. 2024;13(23):1958. DOI: 10.3390/cells13231958
21. Chen X., Li H., Xu C. et al. CYP19A1 is downregulated by BRD4 and suppresses castration-resistant prostate cancer cell invasion and proliferation by decreasing AR expression. Am J Cancer Res. 2023;13(9):4003–4020. PMID: 37818065
22. Liang Z., Cao J., Tian L. et al. Aromatase-induced endogenous estrogen promotes tumour metastasis through estrogen receptor-α/matrix metalloproteinase 12 axis activation in castration-resistant prostate cancer. Cancer Lett. 2019;467:72–84. DOI: 10.1016/j.canlet.2019.09.001
23. Gadkar S., Thakur M., Desouza J. et al. Estrogen receptor expression is modulated in human and mouse prostate epithelial cells during cancer progression. Steroids. 2022;184:109036. DOI: 10.1016/j.steroids.2022.109036
24. Bonkhoff H. Estrogen receptor signaling in prostate cancer: Implications for carcinogenesis and tumor progression. Prostate. 2018;78(1):2–10. DOI: 10.1002/pros.23446
25. Takizawa I., Lawrence M.G., Balanathan P. et al. Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity. Oncotarget. 2015;6(2):604–616. DOI: 10.18632/oncotarget.2820.27
26. Furic L., Lawrence M.G., Risbridger G.P. Pro-tumorigenic role of ERα in prostate cancer cells. Aging (Albany NY). 2015;7(6):356–357.DOI: 10.18632/aging.100769
27. Chakravarty D., Sboner A., Nair S.S. et al. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer. Nat Commun. 2014;5:5383.DOI: 10.1038/ncomms6383
28. Mak P., Li J., Samanta S. et al. Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor β repression. Cell Rep. 2015;10(12):1982–1991. DOI: 10.1016/j.celrep.2015.02.063.30
29. Wu W.-F., Maneix L., Insunza J. et al. Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate. Proc Natl Acad Sci U S A. 2017;114(19):E3816–E3822. DOI: 10.1073/pnas.1702211114
30. McPherson S.J., Hussain S., Balanathan P. et al. Estrogen receptor-beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFalpha mediated. Proc Natl Acad Sci U S A. 2010;107(7):3123–3128. DOI: 10.1073/pnas.0905524107
31. Bonkhoff H., Berges R. The evolving role of oestrogens and their receptors in the development and progression of prostate cancer. Eur Urol. 2009;55(3):533–542. DOI: 10.1016/j.eururo.2008.10.035
32. Mosli H.A., Tolba M.F., Al-Abd A.M. et al. Catechol estrogens induce proliferation and malignant transformation in prostate epithelial cells. Toxicol Lett. 2013;220(3):247–258. DOI: 10.1016/j.toxlet.2013.05.002
33. Mena-Silva D., Alfaro A., León A. et al. Zeolite Nanoparticles Loaded with 2-Methoxystradiol as a Novel Drug Delivery System for the Prostate Cancer Therapy. Int J Mol Sci. 2023;24(13):10967. DOI: 10.3390/ijms241310967.
34. Tolba M.F., Omar H.A., Hersi F. et al. The impact of Catechol-O-methyl transferase knockdown on the cell proliferation of hormone-responsive cancers. Mol Cell Endocrinol. 2019;488:79–88. DOI: 10.1016/j.mce.2019.03.007
35. Hashimoto Y., Shiina M., Maekawa S. et al. Suppressor effect of catechol-O-methyltransferase gene in prostate cancer. PLoS One. 2021;16(9):e0253877. DOI: 10.1371/journal.pone.0253877
36. Liao W., Sui X., Hou G. et al. Trends in estrogen and progesterone receptors in prostate cancer: a bibliometric analysis. Front Oncol. 2023;13:1111296. DOI: 10.3389/fonc.2023.1111296
37. Hou Z., Huang S., Mei Z. et al. Inhibiting 3βHSD1 to eliminate the oncogenic effects of progesterone in prostate cancer. Cell Rep Med. 2022;3(3):100561. DOI: 10.1016/j.xcrm.2022.100561
38. Grindstad T., Richardsen E., Andersen S. et al. Progesterone Receptors in Prostate Cancer: Progesterone receptor B is the isoform associated with disease progression. Sci Rep. 2018;8(1):11358. DOI: 10.1038/s41598-018-29520-5
39. Seki T., Suzuki R., Ohshima S. et al. Liposome-encapsulated progesterone efficiently suppresses B-lineage cell proliferation. Biochem Biophys Rep. 2024;38:101710. DOI: 10.1016/j.bbrep.2024.101710
40. Zhang W.-F., Li T., Lin S.-X. Meta-Analysis of steroid-converting enzymes and related receptors in prostate cancer suggesting novel combined therapies. J Steroid Biochem Mol Biol. 2020;198:105559. DOI: 10.1016/j.jsbmb.2019.105559
41. Azrad M., Zhang K., Vollmer R.T. et al. Prostatic alpha-linolenic acid (ALA) is positively associated with aggressive prostate cancer: a relationship which may depend on genetic variation in ALA metabolism. PLoS One. 2012;7(12):e53104. DOI: 10.1371/journal.pone.0053104
42. Kothapalli K.S.D., Park H.G., Kothapalli N.S.L. et al. FADS2 function at the major cancer hotspot 11q13 locus alters fatty acid metabolism in cancer. Prog Lipid Res. 2023;92:101242. DOI: 10.1016/j.plipres.2023.101242
43. Zhang T., Chen X., Ju X. et al. PPARG is a potential target of Tanshinone IIA in prostate cancer treatment: a combination study of molecular docking and dynamic simulation based on transcriptomic bioinformatics. Eur J Med Res. 2023;28(1):487. DOI: 10.1186/s40001-023-01477-w
44. Elix C., Pal S.K., Jones J.O. The role of peroxisome proliferator-activated receptor gamma in prostate cancer. Asian J Androl. 2018;20(3):238–243. DOI: 10.4103/aja.aja_15_17
45. Galbraith L.C.A., Mui E., Nixon C. et al. PPAR-gamma induced AKT3 expression increases levels of mitochondrial biogenesis driving prostate cancer. Oncogene. 2021;40(13):2355–2366. DOI: 10.1038/s41388-021-01707-7
46. Hisatake J.I., Ikezoe T., Carey M. et al. Down-Regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer. Cancer Res. 2000;60(19):5494–5498. PMID: 11034093
47. Hantusch B., Kenner L., Stanulović V.S. et al. Targeting Androgen, Thyroid Hormone, and Vitamin A and D Receptors to Treat Prostate Cancer. Int J Mol Sci. 2024;25(17):9245. DOI: 10.3390/ijms25179245
48. Zhang Z.-H., Liu M.-D., Yao K. et al. Vitamin D deficiency aggravates growth and metastasis of prostate cancer through promoting EMT in two β-catenin-related mechanisms. J Nutr Biochem. 2023;111:109177. DOI: 10.1016/j.jnutbio.2022.109177
49. Mooso B., Madhav A., Johnson S. et al. Androgen Receptor regulation of Vitamin D receptor in response of castration-resistant prostate cancer cells to 1α-Hydroxyvitamin D5 — a calcitriol analog. Genes Cancer. 2010;1(9):927–940. DOI: 10.1177/1947601910385450
50. Erzurumlu Y., Aydogdu E., Dogan H.K. et al. 1.25(OH)(2) D(3) induced vitamin D receptor signaling negatively regulates endoplasmic reticulum-associated degradation (ERAD) and androgen receptor signaling in human prostate cancer cells. Cell Signal. 2023;103:110577. DOI: 10.1016/j.cellsig.2022.110577
51. Maksymchuk O.V., Kashuba V.I. Altered expression of cytochrome P450 enzymes involved in metabolism of androgens and vitamin D in the prostate as a risk factor for prostate cancer. Pharmacol Rep. 2020;72(5):1161–1172. DOI: 10.1007/s43440-020-00133-y
52. Torkko K., Till C., Tangen C.M. et al. Vitamin D Pathway and Other Related Polymorphisms and Risk of Prostate Cancer: Results from the Prostate Cancer Prevention Trial. Cancer Prev Res (Phila). 2020;13(6):521–530. DOI: 10.1158/1940-6207.CAPR-19-0413
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