MESANE TÜMÖRLÜ HASTALARIN KANLARINDA EPİGENETİK BİYOBELİRTEÇLER OLARAK PROTOKADERİN GEN AİLESİ ÜYELERİ PCDH8, PCDH10 VE PCDH17’NİN ARAŞTIRILMASI

Yıl 2020, Cilt: 22 Sayı: 2, 163 - 171, 31.08.2020

Zeynep Yeğin Filiz Özen Haydar Koç Asıf Yıldırım Recep Büyükalpelli

https://doi.org/10.24938/kutfd.676670

Öz

Amaç: Çalışmanın amacı mesane tümörlü hastalarda ve sağlıklı kontrollerde protokaderin gen ailesine ait olan protokaderin 8 (PCDH8), protokaderin 10 (PCDH10) ve protokaderin 17 (PCDH17) genlerinin periferal kan DNA metilasyon profillerini analiz ederek bu profillerin tümör-spesifik olası etkilerini değerlendirmektir. Araştırılan üç genin metilasyon profiliyle spesifik demografik ve/veya klinikopatolojik veriler arasındaki olası ilişkinin araştırılması da çalışmanın ikinci hedefidir.

Gereç ve Yöntemler: Mesane karsinomalı (n=80; düşük dereceli: 40, yüksek dereceli: 40) ve sağlıklı kontrollerin (n=40) periferal kan örneklerinden ekstrakte edilen genomik DNA promotor bölgelerinin hipermetilasyon analizi için bisülfit modifikasyon ve metilasyon-spesifik PCR işlemine maruz bırakılmıştır.

Bulgular: PCDH8 metilasyon profilinin yaşla birlikte artış gösterdiği gözlenmiştir. Neredeyse kontrollerin tamamında da bu genler bakımından kısmi metilasyon profilleri belirlendiği için hasta örneklerindeki PCDH10 ve PCDH17 metilasyon paternleri bir farklılık oluşturmamakla beraber PCDH8 daha farklı bir kan epigenetik profili sergilemiştir.

Sonuç: PCDH8 geninin kandaki metilasyon modelinin yaşlanma süreciyle ilişkisi çalışmamızda gösterilmiştir. Mesane kanserindeki etkisi açısından daha kesin bir sonuca varabilmek için PCDH8’in kandaki metilasyon durumunun daha yüksek sayılı kohortta ve MethyLight gibi daha duyarlı metotlarla araştırılmasını tavsiye etmekteyiz.

Anahtar Kelimeler

Mesane kanseri, DNA metilasyonu, periferik kan, PCDH8, PCDH10, PCDH17

Destekleyen Kurum

Sinop Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi

Proje Numarası

SHMYO-1901-18-36

Teşekkür

“Bu çalışma Sinop Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimince desteklenmiştir. Proje Numarası: SHMYO-1901-18-36, 2018”

The Investigation of Protocadherin Gene Family Members PCDH8, PCDH10, and PCDH17 as Epigenetic Biomarkers in Blood Samples of Patients with Bladder Tumor

Öz

Objective: The aim of the study was to evaluate the potential tumor-specific effects of peripheral blood DNA methylation profiles of protocadherin 8 (PCDH8), protocadherin 10 (PCDH10), and protocadherin 17 (PCDH17) genes who belong to the protocadherin gene family, in patients with bladder tumors and healthy controls. The potential association between methylation profiles of the investigated three genes and demographic and/or clinicopathologic data was a second target of the study.

Material and Methods: Genomic DNA extracted from peripheral blood samples of patients with bladder carcinoma (n=80; low-grade: 40, high-grade: 40) and healthy controls (n=40) was subjected to bisulphite modification and methylation-specific PCR for hypermethylation analyses of promoter regions.

Results: PCDH8 methylation profile was observed to be increased with age. Though PCDH10 and PCDH17 methylation patterns did not reflect a difference in patients since partial methylation profiles were also almost completely detected in controls; PCDH8 displayed a more different blood epigenetic profile.

Conclusion: The association of blood methylation pattern of PCDH8 with aging process was shown in our study. We recommend the investigation of the status of PCDH8 methylation in blood in larger cohorts and with more sensitive methods such as MethyLight to draw a more precise conclusion in terms of its effect in bladder carcinoma.

Anahtar Kelimeler

Bladder cancer, DNA methylation, peripheral blood, PCDH8,, PCDH10, PCDH17

Proje Numarası

SHMYO-1901-18-36

Kaynakça

• 1. Lin YL, Ma JH, Luo XL, Guan TY, Li ZG. Clinical significance of protokaderin-8 (PCDH8) promotor methylation in bladder cancer. J Int Med Res. 2013;41(1):48-54.
• 2. Luo ZG, Li ZG, Gui SL, Chi BJ, Ma JG. Protokaderin-17 promotor methylation in serum-derived DNA is associated with poor prognosis of bladder cancer. J Int Med Res. 2014;42(1):35-41.
• 3. Zhang D, Zhao W, Liao X, Bi T, Li H, Che X. Frequent silencing of protokaderin 8 by promotor methylation, a candidate tumor suppressor for human gastric cancer. Oncol Rep. 2012;28(5):1785-91.
• 4. Lin YL, Xie PG, Wang L, Ma JG. Aberrant methylation of protokaderin 17 and its clinical significance in patients with prostate cancer after radical prostatectomy. Med Sci Monit. 2014;20:1376-82.
• 5. Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protokaderin. Cell Adh Migr. 2011;5(2):97-105.
• 6. Danese E, Minicozzi AM, Benati M, Montagnana M, Paviati E, Salvagno GL et al. Epigenetic alteration: new insights moving from tissue to plasma- the example of PCDH10 promotor methylation in colorectal cancer. Br J Cancer. 2013;109(3):807-13.
• 7. Qiu C, Bu X, Jiang Z. Protokaderin-10 acts as a tumor suppressor gene, and is frequently downregulated by promotor methylation in pancreatic cancer cells. Oncol Rep. 2016;36(1):383-9.
• 8. Deng QK, Lei YG, Lin YL, Ma JG, Li WP. Prognostic value of protokaderin10 (PCDH10) methylation in serum of prostate cancer patients. Med Sci Monit. 2016;22:516-21.
• 9. Lin YL, Li ZG, He ZK, Guan TY, Ma JG. Clinical and prognostic significance of protokaderin-10 (PCDH10) promotor methylation in bladder cancer. J Int Med Res. 2012;40(6):2117-23.
• 10. Wang XB, Lin YL, Li ZG, Ma JH, Li J, Ma JG. Protokaderin 17 promotor methylation in tumour tissue from patients with bladder transitional cell carcinoma. J Int Med Res. 2014;42(2):292-9.
• 11. 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.
• 12. Miotto E, Sabbioni S, Veronese A, Calin GA, Gullini S, Liboni A et al. Frequent aberrant methylation of the CDH4 gene promotor in human colorectal and gastric cancer. Cancer Res. 2004;64(22):8156-9.
• 13. Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD et al. Global DNA Methylation Level in Whole Blood as a Biomarker in Head and Neck Squamous Cell Carcinoma. Cancer Epidemiol Biomarkers Prev. 2007;16(1).
• 14. Wong EM, Southey MC, Fox SB, Brown MA, Dowty JG, Jenkins MA et al. Constitutional methylation of the BRCA1 promotor is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila). 2011;4(1):23-33.
• 15. Marsit CJ, Koestler DC, Christensen BC, Karagas MR, Houseman EA, Kelsey KT. DNA methylation array analysis identifies profiles of blood-derived DNA methylation associated with bladder cancer. J Clin Oncol. 2011;29(9):1133-9.
• 16. Brennan K, Garcia-Closas M, Orr N, Fletcher O, Jones M, Ashworth A et al. Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. Cancer Res. 2012;72(9):2304-13.
• 17. Tahara T, Maegawa S, Chung W, Garriga J, Jelinek J, Estécio MR et al. Examination of whole blood DNA methylation as a potential risk marker for gastric cancer. Cancer Prev Res (Phila). 2013;6(10):1093-100.
• 18. Zhang P, Wang H, Wang J, Liu Q, Wang Y, Feng F et al. Association between protocadherin 8 promoter hypermethylation and the pathological status of prostate cancer. Oncol Lett. 2017;14(2):1657-64.
• 19. Miyamoto K, Fukutomi T, Akashi-Tanaka S, Hasegawa T, Asahara T, Sugimura T et al. Identification of 20 Genes Aberrantly Methylated in Human Breast Cancers. Int J Cancer. 2005;116(3):407-14.