Berna DEMİRCAN, Asıf YILDIRIM, Özgür EFİLOĞLU, Hatice İKİIŞIK, Burcu YÜCEL, Alper KAYA, Aslı KARAMAN, Ahsen Merve BAYRAK

Investigation of Methylation Status of Homeobox D3 (HOXD3) and Protocadherin 17 (PCDH17) in Patients with Prostate Cancer

OBJECTIVE Prostate cancer is one of the most common cancers in male gender. Despite recent advances in the diagnosis and the treatment methods, more reliable molecular biomarkers have been needed for the diagnosis and evaluation of response to treatments such as chemotherapy, anti-androgen therapy, and radiotherapy. The aim of this study is to investigate promoter methylation status of HOX3D and PCDH17 genes in prostate cancer in Turkish population. METHODS A total of 46 patients with prostate cancer were included in this study. Tissue samples obtained from 36 patients with benign prostate hyperplasia were used as controls. Methylation status of HOXD3 and PCDH17 genes was determined by quantitative Methylation-Specific PCR with commercially available primer sets. RESULTS Both HOXD3 and PCDH17 promoter methylation was determined significantly higher in patients with compare to controls (p=0.0198 and p=0.0386, respectively). A significant but weak correlation was found between methylation status and pre-operative PSA level for HOXD3 (Spearman’s rho=0.259, p=0.02) and PCDH17 gene (Spearman’s rho=0.324, p=0.006). CONCLUSION Our results indicated that HOXD3 and PCDH17 promoter methylation levels are higher in patients with prostate cancer. Further studies with large sample cohorts and clinicopathological data will enlighten presumptive role of HOXD3 and PCDH17 methylation status.

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1. Rawla P. Epidemiology of prostate cancer. World J Oncol 2019;10(2):63–89.
2. Culp MB, Soerjomataram I, Efstathiou JA, Bray F, Jemal A. Recent global patterns in prostate cancer incidence and mortality rates. Eur Urol 2020;77(1):38–52.
3. Pernar CH, Ebot EM, Wilson KM, Mucci LA. The epidemiology of prostate cancer. Harb Cold Spring Perspect Med 2018;8(12):a030361.
4. Litwin MS, Tan HJ. The diagnosis and treatment of prostate cancer: A review. JAMA 2017;317(24):2532– 42.
5. Tikkinen KA, Dahm P, Lytvyn L, Heen AF, Vernooij RW, Siemieniuk RA, et al. Prostate cancer screening with prostate-specific antigen (PSA) test: A clinical practice guideline. BMJ (Online) 2018;362:k3581.
6. Thompson IM, Ankerst DP, Chi C, Goodman PJ, Tangen CM, Lucia MS, et al. Assessing prostate cancer risk: Results from the prostate cancer prevention trial. J Natl Cancer Inst 2006;98(8):529–34.
7. Sartor O, de Bono JS. Metastatic prostate cancer. N Engl J Med 2018;378(7):645–57.
8. D’Amico AV, Whittington R, Malkowicz SB, Wu YH, Chen M, Art M, et al. Combination of the preoperative PSA level, biopsy Gleason score, percentage of positive biopsies, and MRI T-stage to predict early PSA failure in men with clinically localized prostate cancer. Urology 2000;55(4):572–7.
9. Nebbioso A, Tambaro FB, Dell’Aversana C, Altucci L. Cancer epigenetics: Moving forward. PLoS Genet 2018;14(6):e1007362.
10.Yegnasubramanian S, de Marzo AM, Nelson WG. Prostate cancer epigenetics: From basic mechanisms to clinical implications. Cold Spring Harb Perspect Med 2019;9(4):a030445.
11.Wu Y, Sarkissyan M, Vadgama JV. Epigenetics in breast and prostate cancer. Methods Mol Biol 2015;1238:425– 66.
12.Cooper CS, Foster CS. Concepts of epigenetics in prostate cancer development. 2009;100(2):240-5. 13.Schulz WA, Hatina J. Epigenetics of prostate cancer: Beyond DNA methylation. J Cell Mol Med. 2006;10(1):100–25.
14.Cillo C, Faiella A, Cantile M, Boncinelli E. Homeobox genes and cancer. Exp Cell Res 1999;248(1):1–9.
15.Vega-Benedetti AF, Loi E, Moi L, Blois S, Fadda A, Antonelli M, et al. Clustered protocadherins methylation alterations in cancer. Clin Epigenet 2019;11(1):100.
16.Strand SH, Orntoft TF, Sorensen KD. Prognostic DNA methylation markers for prostate cancer. Int J Mol Sci 2014;15(9):16544–76.
17.Jerónimo C, Bastian PJ, Bjartell A, Carbone GM, Catto JW, Clark SJ, et al. Epigenetics in prostate cancer: Biologic and clinical relevance. Eur Urol. 2011;60(4):753– 66.
18.Su J, Huang YH, Cui X, Wang X, Zhang X, Lei Y, et al. Homeobox oncogene activation by pan-cancer DNA hypermethylation. Genome Biol 2018;19(1):108.
19.Abate-Shen C. Deregulated homeobox gene expression in cancer: Cause or consequence? Nat Rev Cancer 2002;2(10):777–85.
20.Kron KJ, Liu L, Pethe VV, Demetrashvili N, Nesbitt ME, Trachtenberg J, et al. DNA methylation of HOXD3 as a marker of prostate cancer progression. Lab Investig 2010;90(7):1060–7.
21.Liu L, Kron KJ, Pethe VV, Demetrashvili N, Nesbitt ME, Trachtenberg J, et al. Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression. Int J Cancer 2011;129(10):2454–62.
22.Savio AJ, Kamdar S, Jeyapala R, Olkhov-Mitsel E, Cuizon C, Finelli A, et al. Methylation markers in prostate biopsies are prognosticators for late biochemical recurrence and therapy after surgery in prostate cancer patients. J Mol Diagn 2020;22(1):30–9.
23.Pancho A, Aerts T, Mitsogiannis MD, Seuntjens E. Protocadherins at the crossroad of signaling pathways. Front Mol Neurosci 2020;13:117.
24.Giefing M, Zemke N, Brauze D, Kostrzewska-Poczekaj M, Luczak M, Szaumkessel M, et al. High resolution ArrayCGH and expression profiling identifies PTPRD and PCDH17/PCH68 as tumor suppressor gene candidates in laryngeal squamous cell carcinoma. Genes Chromosomes Cancer 2011;50(3):154–66.
25.Costa VL, Henrique R, Danielsen SA, Eknaes M, Patrício P, Morais A, et al. TCF21 and PCDH17 methylation: An innovative panel of biomarkers for a simultaneous detection of urological cancers. Epigenetics 2011;6(9):1120–30.
26.Wang XB, Lin YL, Li ZG, Ma JH, Li J, Ma JG. Protocadherin 17 promoter methylation in tumour tissue from patients with bladder transitional cell carcinoma. J Int Med Res 2014;42(2):292–9.
27.Hu X, Sui X, Li L, Huang X, Rong R, Su X, et al. Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol 2013;229(1):62–73.
28.Lin YL, Xie PG, Wang L, Ma JG. Aberrant methylation of protocadherin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy. Med Sci Monit 2014;20:1376–82.