NRAMP1 and hGPX1 Gene Polymorphism and Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer

• Published in: European urology Vol. 59; no. 3; pp. 430 - 437
• Main Authors: Chiong, Edmund, Kesavan, Arshvin, Mahendran, Ratha, Chan, Yiong Huak, Sng, Jen Hwei, Lim, Yew Koon, Kamaraj, Revathi, Tan, Theresa M.C, Esuvaranathan, Kesavan
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier 01-03-2011
• Subjects: Administration, Intravesical; Adult; Aged; Aged, 80 and over; Bacterial diseases; BCG Vaccine - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - genetics; Cation Transport Proteins - genetics; Female; Follow-Up Studies; Glutathione Peroxidase - genetics; Glutathione Peroxidase GPX1; Human bacterial diseases; Humans; Immunologic Factors - administration & dosage; Infectious diseases; Interferon-alpha - administration & dosage; Male; Medical sciences; Middle Aged; Mycobacterium tuberculosis; Neoplasm Invasiveness; Neoplasm Recurrence, Local - genetics; Nephrology. Urinary tract diseases; Polymorphism, Restriction Fragment Length; Predictive Value of Tests; Prognosis; Promoter Regions, Genetic - genetics; Treatment Outcome; Tuberculosis and atypical mycobacterial infections; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urinary tract. Prostate gland; Urology; Bacillus Calmette-Guérin; Bladder cancer; Gene polymorphism; Nephrology; Urinary system disease; Genetic variability; BCG; Genotype; Urinary tract disease; Malignant tumor; Urology; Natural resistance associated macrophage protein 1; Treatment; Bladder disease; Cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2010.11.031

Abstract Background The natural resistance-associated macrophage protein 1 ( NRAMP1 ) gene is associated with susceptibility to Mycobacterium tuberculosis in humans and to bacillus Calmette-Guérin (BCG) in mice. The detoxification enzyme, human glutathione peroxidase 1 (hGPX1), is associated with recurrence of bladder cancer (BCa). Objective To determine whether NRAMP1 and hGPX1 gene polymorphisms correlate with response to BCG immunotherapy for non–muscle-invasive BCa (NMIBC). Design, setting, and participants DNA was obtained from the peripheral blood of 99 NMIBC patients who were prospectively randomized to receive postresection intravesical BCG (81 mg [ n = 50] or 27 mg [ n = 19]) or BCG (27 mg) with interferon alpha (IFN-α; n = 30). The median follow-up time was 60 mo. Intervention Intravesical BCG or BCG–IFN-α. Measurements Restriction fragment length polymorphism (RFLP) analysis was performed to identify polymorphisms in the NRAMP1 promoter region (GT repeat number) and at position 543 (aspartate [D] and/or asparagine [N] expression) within the NRAMP1 protein (D543N) and position 198 (proline and/or leucine expression) within the hGPX1 protein (Pro198Leu). Data were analyzed using χ2 analysis, multivariate analysis, and Kaplan-Meier curves. Results and limitations On univariate analysis, the NRAMP1 D543N G:G genotype had decreased cancer-specific survival (CSS; p = 0.036). The hGPX1 CT genotype (Pro-Leu) had decreased recurrence time ( p = 0.03) after BCG therapy. On multivariate analysis, patients with the NRAMP1 D543N G:G genotype and allele 3GT n polymorphism had decreased recurrence time ( p = 0.014 and p = 0.03) after BCG therapy. The limitation of this study was its small sample size. Conclusions Polymorphisms of the NRAMP1 and hGPX1 genes may be associated with recurrence of BCa after BCG immunotherapy.