MP65-11 RNA SEQUENCING IDENTIFIES 3 DIFFERENT MOLECULAR GRADES AND IMMUNE CHECKPOINT CASCADES WITH DISTINCT CLINICAL BEHAVIOUR IN NON MUSCLE INVASIVE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology III1 Apr 2018MP65-11 RNA SEQUENCING IDENTIFIES 3 DIFFERENT MOLECULAR GRADES AND IMMUNE CHECKPOINT CASCADES WITH DISTINCT CLINICAL BEHAVIOUR IN NON MUSCLE INVASIVE BLADDER CANCER Thenappan Chandrasekar, Alexandre R Zlotta, Jess Shen, Aidan P Noon, Haiyan Jiang, Annette Erlich, Cynthia Kuk, Ruoyu Ni, Balram Sukhu, Kin Chan, Morgan Roupret, Thomas Seisen, Eva Comperat, Joan Sweet, Girish Kulkarni, Neil Fleshner, Azar Azad, Theodorus H van der Kwast, and Jeffrey Wrana Thenappan ChandrasekarThenappan Chandrasekar More articles by this author , Alexandre R ZlottaAlexandre R Zlotta More articles by this author , Jess ShenJess Shen More articles by this author , Aidan P NoonAidan P Noon More articles by this author , Haiyan JiangHaiyan Jiang More articles by this author , Annette ErlichAnnette Erlich More articles by this author , Cynthia KukCynthia Kuk More articles by this author , Ruoyu NiRuoyu Ni More articles by this author , Balram SukhuBalram Sukhu More articles by this author , Kin ChanKin Chan More articles by this author , Morgan RoupretMorgan Roupret More articles by this author , Thomas SeisenThomas Seisen More articles by this author , Eva ComperatEva Comperat More articles by this author , Joan SweetJoan Sweet More articles by this author , Girish KulkarniGirish Kulkarni More articles by this author , Neil FleshnerNeil Fleshner More articles by this author , Azar AzadAzar Azad More articles by this author , Theodorus H van der KwastTheodorus H van der Kwast More articles by this author , and Jeffrey WranaJeffrey Wrana More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2077AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Non muscle invasive bladder cancer (NMIBC) has a highly variable clinical behaviour not adequately predicted by their histological grade and clinical parameters. Some are indolent; others quickly progress to muscle-invasive disease. The discrepancy between phenotype and genotype is compounded further by interobserver variability in pathological grading. There is an unmet need to improve the prediction of NMIBC's behavior. METHODS Whole transcriptomic (WT) analysis of 178 bladder tumours (158 NMIBC and 20 MIBC or metastatic) was performed from formalin fixed paraffin embedded (FFPE) tissues incorporating messenger RNA expression, splice variants, gene fusion, mutation detection and immune checkpoint inhibitor cascades. CTLA, PD-1, LAG3, TIM3, TIGIT and B7 were compiled as an index with all major genes in the cascade included. These data were integrated and tested for correlations with both pathological grading and clinical outcomes. Conventional pathological grading for both WHO 1973 (grade 1, 2 and 3) and 2004 (low grade-LG vs high grade-HG) classifications was reviewed by 3 different expert uro-pathologists and kappa statistic for interobserver variability was calculated. For validation we used an independent RNA-Sequencing dataset (n=209, Hedegaard et al. 2016 Cancer Cell). RESULTS Unsupervised clustering of data from RNA-Seq distinguished three molecular subtypes of NMIBC termed Molecular Grade Related Index (MGRI) 1, MGRI2 and MGRI3. MGRI1 comprised of almost exclusively LG tumours, while MGRI3 clustered with HG MIBC tumours. After assessment by expert pathologists, kappa for interobserver variability in 1973 WHO histological grading was only 0.40 and 0.78 for the 2004 classification. FGFR3 mutations, FGFR3::TACC3 fusion events and MGRI1 genes were strongly associated with components of xenobiotic metabolism (p=2.51x10-09) signalling systems, in particular, GTPase regulation (p=0.002), respiratory cycle genes (p=0.004) and a HOX cluster (p=0.005). MGRI independently predicted progression to MIBC (n=138, HR=2.96, 95%CI=1.70-5.13, p=1.20x10-04). Five year progression-free survival in a combined data set (n=347) differed significantly for MGRI1 (100%) vs MGRI2 (92.2%) vs MGRI3 (73.5%, p=1.99x10-05, Gray's test). PD-1 Immune Checkpoint Cascade, was an independent predictor of progression (OR 2.85, p<0.05). CONCLUSIONS RNA sequencing delineates three molecular classes of NMIBC with different risks of progression to muscle invasion, compared to conventional histologic grading. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e863 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Thenappan Chandrasekar More articles by this author Alexandre R Zlotta More articles by this author Jess Shen More articles by this author Aidan P Noon More articles by this author Haiyan Jiang More articles by this author Annette Erlich More articles by this author Cynthia Kuk More articles by this author Ruoyu Ni More articles by this author Balram Sukhu More articles by this author Kin Chan More articles by this author Morgan Roupret More articles by this author Thomas Seisen More articles by this author Eva Comperat More articles by this author Joan Sweet More articles by this author Girish Kulkarni More articles by this author Neil Fleshner More articles by this author Azar Azad More articles by this author Theodorus H van der Kwast More articles by this author Jeffrey Wrana More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...