The impact of genetic polymorphism on CYP19A1 in androgen-deprivation therapy among Japanese men
- 49 Downloads
Inadequate suppression of testosterone during androgen-deprivation therapy impairs its efficacy. This study investigated the significance of genetic polymorphism in CYP19A1, which encodes aromatase that catalyzes androgens into estrogens, among men treated with primary ADT for metastatic prostate cancer.
This study included 80 Japanese patients with metastatic prostate cancer whose serum testosterone levels during ADT were available. The association of CYP19A1 gene polymorphism (rs1870050) with clinicopathological parameters including serum testosterone levels during ADT as well as progression-free survival and overall survival was examined.
Serum testosterone levels during ADT of men carrying homozygous wild-type (AA) in the CYP19A1 gene [median (interquartile range); 11.6 (8.3–20.3) ng/dl] were higher than those in men carrying the heterozygous/homozygous variant (AC/CC) [median (interquartile range); 10.0 (6.4–12.8) ng/dl]. When adjusted by Gleason score, initial PSA, M-stage and serum testosterone level during ADT, heterozygous/homozygous variant (AC/CC) in the CYP19A1 gene was associated with a lower risk of progression to castration resistance [hazard ratio (95% confidence interval), 0.53 [0.29–0.92], p = 0.025], but not to any-cause death [hazard ratio (95% confidence interval), 0.74 [0.36–1.49], p = 0.40].
These findings suggest that genetic variation in CYP19A1 (rs1870050) might affect the prognosis of patients with metastatic prostate cancer when treated with ADT by regulating serum testosterone levels.
KeywordsAndrogen-deprivation therapy Aromatase CYP19A1 Prostate cancer Testosterone
We would like to thank Ms. Noriko Hakoda and Ms. Eriko Gunshima for technical assistance, and Edanz Group Japan for editorial assistance. We particularly thank Dr. Hiroyuki Masaoka (Kyushu University, Fukuoka, Japan) for excellent advices for statistical analyses.
This work was supported by JSPS KAKENHI grant (17K11145) and Research Promotion Grant from Shin-Nihon Foundation of Advanced Medical Research.
Compliance with ethical standards
Conflict of interest
The authors have no conflict of interest to declare.
IRB approval from Kyushu University.
- 2.Klotz L, O’Callaghan C, Ding K, Toren P, Dearnaley D, Higano CS, Horwitz E, Malone S, Goldenberg L, Gospodarowicz M, Crook JM (2015) Nadir testosterone within first year of androgen-deprivation therapy (ADT) predicts for time to castration-resistant progression: a secondary analysis of the PR-7 trial of intermittent versus continuous ADT. J Clin Oncol 33:1151–1156CrossRefGoogle Scholar
- 3.Shiota M, Fujimoto N, Yokomizo A, Takeuchi A, Kashiwagi E, Dejima T, Kiyoshima K, Inokuchi J, Tatsugami K, Eto M (2016) The prognostic impact of serum testosterone during androgen-deprivation therapy in patients with metastatic prostate cancer and the SRD5A2 polymorphism. Prostate Cancer Prostatic Dis 19:191–196CrossRefGoogle Scholar
- 5.Shiota M, Fujimoto N, Takeuchi A, Kashiwagi E, Dejima T, Inokuchi J, Tatsugami K, Yokomizo A, Kajioka S, Uchiumi T, Eto M (2018) The association of polymorphisms in the gene encoding gonadotropin-releasing hormone with serum testosterone level during androgen deprivation therapy and prognosis of metastatic prostate cancer. J Urol 199:734–740CrossRefGoogle Scholar
- 10.Travis RC, Schumacher F, Hirschhorn JN, Kraft P, Allen NE, Albanes D, Berglund G, Berndt SI, Boeing H, Bueno-de-Mesquita HB, Calle EE, Chanock S, Dunning AM, Hayes R, Feigelson HS, Gaziano JM, Giovannucci E, Haiman CA, Henderson BE, Kaaks R, Kolonel LN, Ma J, Rodriguez L, Riboli E, Stampfer M, Stram DO, Thun MJ, Tjønneland A, Trichopoulos D, Vineis P, Virtamo J, Le Marchand L, Hunter DJ (2009) CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 18:2734–2744CrossRefGoogle Scholar
- 11.Kanda S, Tsuchiya N, Narita S, Inoue T, Huang M, Chiba S, Akihama S, Saito M, Numakura K, Tsuruta H, Satoh S, Saito S, Ohyama C, Arai Y, Ogawa O, Habuchi T (2015) Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival. Int J Cancer 136:74–82CrossRefGoogle Scholar
- 15.Shiota M, Fujimoto N, Imada K, Yokomizo A, Itsumi M, Takeuchi A, Kuruma H, Inokuchi J, Tatsugami K, Uchiumi T, Oda Y, Naito S (2016) Potential role for YB-1 in castration-resistant prostate cancer and resistance to enzalutamide through the androgen receptor V7. J Natl Cancer Inst 108:djw005CrossRefGoogle Scholar
- 16.Shiota M, Fujimoto N, Itsumi M, Takeuchi A, Inokuchi J, Tatsugami K, Yokomizo A, Kajioka S, Uchiumi T, Eto M (2017) Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress. Ann Oncol 28:569–575Google Scholar
- 17.International Union Against Cancer (1997) Urologic tumors. Prostate. In: Sobin LH, Wittekind CH (eds) TNM classification of malignant tumors, 5th edn. Wiley, New York, pp 170–173Google Scholar
- 18.Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M, Prostate Cancer Clinical Trials Working Group (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148–1159CrossRefGoogle Scholar
- 19.Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, Özgüroğlu M, Ye D, Feyerabend S, Protheroe A, De Porre P, Kheoh T, Park YC, Todd MB, Chi KN, LATITUDE Investigators (2017) Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377:352–360CrossRefGoogle Scholar
- 20.James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, Ritchie AWS, Amos CL, Gilson C, Jones RJ, Matheson D, Millman R, Attard G, Chowdhury S, Cross WR, Gillessen S, Parker CC, Russell JM, Berthold DR, Brawley C, Adab F, Aung S, Birtle AJ, Bowen J, Brock S, Chakraborti P, Ferguson C, Gale J, Gray E, Hingorani M, Hoskin PJ, Lester JF, Malik ZI, McKinna F, McPhail N, Money-Kyrle J, O’Sullivan J, Parikh O, Protheroe A, Robinson A, Srihari NN, Thomas C, Wagstaff J, Wylie J, Zarkar A, Parmar MKB, Sydes MR, STAMPEDE Investigators (2017) Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377:338–351CrossRefGoogle Scholar