Genetic Association Study of Two Variants within RFX6 and SLC22A3 for Their Potential Role in Prostate Cancer Predisposition

Document Type : Research Articles

Authors

• Setare Kakavand ¹
• Seyed Abdolhamid Angaji ²
• Behnaz Beikzadeh ³
• Raheleh Roudi ⁴
• Behzad Narouie ⁵

¹ Department of Biological Sciences, North Tehran Branch Islamic Azad University, Tehran, Iran

² Department of Cell and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

³ Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

⁴ Department of Radiology, Stanford University, Stanford, CA 94305, USA

⁵ Department of Urology, Zahedan University of Medical Sciences, Zahedan, Iran

https://doi.org/10.22067/jcmr.2023.81874.1064

Abstract

Prostate cancer is one of the leading causes of cancer-related deaths among men worldwide. Research has shown that genetic variations can increase an individual's risk of developing this disease. In this study, we investigated the potential role of two genetic variants, one within RFX6 and another within SLC22A3, in predisposition to prostate cancer. A genetic association study was conducted, involving a case-control design with 112 prostate cancer cases and 95 individuals affected by benign prostatic hyperplasia who served as controls and had no history of cancer. The genotypes of the two variants, rs339331 in RFX6 and rs9364554 in SLC22A3, were determined using tetra-primer ARMS-PCR. In this study, a multi-stage strategy was employed to analyze the data obtained from genotyping and to assess the association of these two variants with prostate cancer risk. For statistical analysis, Chi-squared, Fisher’s exact test and logistic regression were performed to evaluate the association of variants with prostate cancer and Gleason score. The results suggest that the rs9364554 variant in SLC22A3 is not associated with prostate cancer risk under either additive or multiplicative genetic models, while the variant in RFX6 is significantly associated with prostate cancer susceptibility. The TT genotype of rs339331 indicated a possible protective effect against prostate adenocarcinoma (CI 95% = 0/009 -0/725, P-value = 0/009, OR = 0/083). In conclusion, our study provides evidence that the genetic variant rs339331 within RFX6 is significantly associated with prostate cancer susceptibility and may have a potential protective effect against prostate adenocarcinoma. It should be mentioned that more research is needed to investigate the possible protective effect of the TT genotype of rs9364554 against prostate cancer risk in other populations and various ethnic groups and particularly larger sample sizes are required to confirm this association.

Keywords

• Prostate Cancer
• SLC22A3
• RFX6
• Variant
• Benign prostatic hyperplasia (BPH)

20.1001.1.20089147.2023.14.2.7.3

References

Allemailem K. S., Almatroudi A., Alrumaihi F., Makki Almansour N., Aldakheel F. M., Rather R. A., et al. (2021) Single nucleotide polymorphisms (SNPs) in prostate cancer: its implications in diagnostics and therapeutics. Am J Transl Res 13:3868-3889.

Andreoiu M. and Cheng L. (2010) Multifocal prostate cancer: biologic, prognostic, and therapeutic implications. Human Pathology 41:781-793.

Bleyer A., Spreafico F. and Barr R. (2020) Prostate cancer in young men: An emerging young adult and older adolescent challenge. Cancer 126:46-57.

Boyle H. J., Alibhai S., Decoster L., Efstathiou E., Fizazi K., Mottet N., et al. (2019) Updated recommendations of the International Society of Geriatric Oncology on prostate cancer management in older patients. European Journal of Cancer 116:116-136.

Chen L., Hong C., Chen E. C., Yee S. W., Xu L., Almof E. U., et al. (2013) Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3. Pharmacogenomics Journal 13:110-120.

Daram S., Poornima S., Zubeda S., P A., V a., Boppana S., Prabhala S., A S. and D R. (2020) Association of Regulatory Factor X 6 gene (rs339331) polymorphism with Prostate Cancer: A case-control study from South India.  2019(5).

Farhood B., Geraily G. and Alizadeh A. (2018) Incidence and Mortality of Various Cancers in Iran and Compare to Other Countries: A Review Article. Iranian Journal of Public Health 47:309-316.

Gandaglia G., Abdollah F., Schiffmann J., Trudeau V., Shariat S. F., Kim S. P., et al. (2014) Distribution of metastatic sites in patients with prostate cancer: A population-based analysis. Prostate 74:210-216.

Grisanzio C., Werner L., Takeda D., Awoyemi B. C., Pomerantz M. M., Yamada H., et al. (2012) Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 109:11252-11257.

Huang Q., Whitington T., Gao P., Lindberg J. F., Yang Y., Sun J., et al. (2014) A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nature Genetics 46:126-135.

Ilic D., Djulbegovic M., Jung J. H., Hwang E. C., Zhou Q., Cleves A., et al. (2018) Prostate cancer screening with prostate-specific antigen (PSA) test: a systematic review and meta-analysis. BMJ 362:k3519.

Jiang Y., Meyers T. J., Emeka A. A., Cooley L. F., Cooper P. R., Lancki N., et al. (2022) Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment. HGG Adv 3.

Jin K., Qiu S., Jin H., Zheng X., Zhou X., Jin D., et al. (2020) Survival Outcomes for Metastatic Prostate Cancer Patients Treated With Radical Prostatectomy or Radiation Therapy: A SEER-based Study. Clinical Genitourinary Cancer 18:e705-e722.

Langan R. C. (2019) Benign Prostatic Hyperplasia. Primary Care: Clinics in Office Practice 46:223-232.

Li B., Huang Q. and Wei G.-H. (2019) The Role of HOX Transcription Factors in Cancer Predisposition and Progression. Cancers 11:528.

Pakzad R., Mohammadian-Hafshejani A., Ghoncheh M., Pakzad I. and Salehiniya H. (2015) The incidence and mortality of prostate cancer and its relationship with development in Asia. Prostate Int 3:135-140.

Park J. W., Lee J. K., Phillips J. W., Huang P., Cheng D., Huang J. and Witte O. N. (2016) Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay. Proceedings of the National Academy of Sciences of the United States of America 113:4482-4487.

Rawla P. (2019) Epidemiology of Prostate Cancer. World Journal of Oncology 10:63-89.

Shore N. (2014) Management of early-stage prostate cancer. American Journal of Managed Care 20:S260-272.

Sulekha Suresh D. and Guruvayoorappan C. (2023) Molecular principles of tissue invasion and metastasis. American Journal of Physiology: Cell Physiology 324:C971-c991.

Wang D., Li Y., Ge H., Ghadban T., Reeh M. and Güngör C. (2022) The Extracellular Matrix: A Key Accomplice of Cancer Stem Cell Migration, Metastasis Formation, and Drug Resistance in PDAC. Cancers 14:3998.

Wong S. K., Mohamad N. V., Giaze T. R., Chin K. Y., Mohamed N. and Ima-Nirwana S. (2019) Prostate Cancer and Bone Metastases: The Underlying Mechanisms. International Journal of Molecular Sciences 20.

Yang W., Liu A., Wu J. and Niu M. (2018) Prostatic stromal sarcoma: A case report and literature review. Medicine (Baltimore) 97:e0495.