MP34-08 CTLA4 SINGLE NUCLEOTIDE POLYMORPHISMS CORRELATE WITH RESPONSE TO BCG IMMUNOTHERAPY (2014)

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2014MP34-08 CTLA4 SINGLE NUCLEOTIDE POLYMORPHISMS CORRELATE WITH RESPONSE TO BCG IMMUNOTHERAPY Ratha Mahendran, Sin Mun Tham, Juwita Rahmat, Jen Hwei Sng, Yew Koon Lim, Lata Raman, Ma Zin Mar Wai, Woon Chau Tsang, Edmund Chiong, Yiong Huak Chan, and Kesavan Esuvaranathan Ratha MahendranRatha Mahendran More articles by this author , Sin Mun ThamSin Mun Tham More articles by this author , Juwita RahmatJuwita Rahmat More articles by this author , Jen Hwei SngJen Hwei Sng More articles by this author , Yew Koon LimYew Koon Lim More articles by this author , Lata RamanLata Raman More articles by this author , Ma Zin Mar WaiMa Zin Mar Wai More articles by this author , Woon Chau TsangWoon Chau Tsang More articles by this author , Edmund ChiongEdmund Chiong More articles by this author , Yiong Huak ChanYiong Huak Chan More articles by this author , and Kesavan EsuvaranathanKesavan Esuvaranathan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1021AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Though BCG is the gold standard for NMIBC there is a significant non responder rate. The reasons for this are not yet established though single nucleotide polymorphisms (SNPs) in certain genes have been found to correlate with response to therapy. In a clinical study bladder cancer patients who were treated with anti-CTLA4 antibodies had increased CD4+ICOShi IFNγ expressing T cells over Treg cell numbers in the bladder and peripheral blood indicating a role for CTLA4 in immunosuppression in bladder cancer patients. Further in a mouse model of orthotopic bladder cancer we found that the presence of tumor induced CTLA4 expression in the bladder. Therefore we evaluated seven SNPs in the CTLA4 gene (Rs733618, Rs4553808, Rs5742909, Rs231775, Rs3087243, Rs7565213, Rs960792) that regulate protein expression and function were chosen for analysis. METHODS We analyzed SNPs in n=138 bladder cancer patients who had previously been treated with BCG and for whom long term follow-up data was available. We also examined n=146 healthy controls. Genomic DNA was extracted and subjected to PCR and followed by High resolution melting (HRM) PCR analysis to identify the SNPs. These were confirmed by sequencing. RESULTS There were no difference in the incidence of SNPs between healthy controls and patients. By Kaplan Meier analysis GA at Rs4553808 (148 months for GA vs 110 months AA) and CT at Rs5742909 (167 months for CT vs 106 months for CC) correlated with longer time to recurrence. By COX regression analysis, CT at Rs5742909; AA at Rs3087243; AA and AG Rs7565213 and TT at Rs960792 were significantly correlated with reduced risk of recurrence (p<0.05). While GA at Rs3087243 and TT at Rs7565213 correlated with a reduced risk of progression (p<0.05); GA at Rs231775 correlated with an increased risk of progression (p<0.05, HR 39.4, 95% CI 1.97-795.84). Increased survival was observed in patients with CT at Rs5742909 (p<0.05). CONCLUSIONS It was previously reported that in Asians Rs231775 GG and GA are associated with decreased risk of cancer. Rs231775 GG unlike the AA genotype is associated with significantly higher T cell activation. Here, Rs231775 GA associated with an increased risk of disease progression but not AA which is expressed at a lower level in our population. These results indicate that for some bladder cancer patients, CTLA4 blockade may be a beneficial co-therapy. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e364 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Ratha Mahendran More articles by this author Sin Mun Tham More articles by this author Juwita Rahmat More articles by this author Jen Hwei Sng More articles by this author Yew Koon Lim More articles by this author Lata Raman More articles by this author Ma Zin Mar Wai More articles by this author Woon Chau Tsang More articles by this author Edmund Chiong More articles by this author Yiong Huak Chan More articles by this author Kesavan Esuvaranathan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...