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Molecular tumour grading and classification of non muscle invasive bladder cancer based on whole transcriptome analysis
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
128
Molecular tumour grading and classification of non muscle invasive bladder cancer based on whole transcriptome analysis Eur Urol Suppl 2017; 16(3);e212
Zlotta A.R.1, Shen J.2, Noon A.3, Jiang H.4, Kuk C.1, Ni R.5, Sukhu B.5, Chan K.2, Erlich A.1, Roupret M.6, Seisen T.6, Comparat E.7, Sweet J.8, Kulkarni G.S.9, Fleshner N.E.9, Azad A.5, Van Der Kwast T.H.8, Wrana J.L.2 1
Mount Sinai Hospital, Dept. of Surgery (urology), Toronto, Canada, 2Mount Sinai Hospital, LunenfeldTanenbaum Research Institute, Toronto, Canada, 3University of Sheffield, Dept. of Urology, Sheffield, United Kingdom, 4University Health Network, Dept. of Statistics, Toronto, Canada, 5Mount Sinai Hospital, Dept. of Pathology and Laboratory Medicine, Toronto, Canada, 6Groupe Hospitalier La PitiéSalpêtière, Université Pierre Et Marie Curie, Dept. of Urology, Paris, France, 7Groupe Hospitalier La PitiéSalpêtière, Université Pierre Et Marie Curie, Dept. of Pathology, Paris, France, 8Toronto General Hospital, University Health Network, Dept. of Pathology, Toronto, Canada, 9Princess Margaret Cancer Centre, University Health Network, Dept. of Surgical Oncology, Urology, Toronto, Canada INTRODUCTION & 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. MATERIAL & METHODS: Whole transcriptomic (WT) analysis of 184 bladder tumours (164 NMIBC and 20 MIBC or metastatic) was performed from formalin fixed paraffin embedded (FFPE) tissues incorporating messenger RNA expression, splice variants, gene fusion and mutation detection. In NMIBC, we used a discovery (n=40) and 2 validation cohorts (n= 40 and 84). 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. RESULTS: Unsupervised clustering of data from RNA sequencing revealed classification of three robustnon-overlapping molecular subtypes of NMIBC termed Grade Related Index (GRI) 1, GRI2 and GRI3. GRI1 comprised of almost exclusively LG tumours, while GRI3 clustered with HG MIBC tumours. After assessment by expert pathologists, kappa for interobserver variability in 1973 WHO histological grading was 0.40 whereas it reached 0.78 for the 2004 classification. Most discrepant cases clustered in molecular subtype GRI2. GRI subclassification independently predicted disease progression in NMIBC and outperformed the established risk EORTC calculator (AUC=0.83 vs 0.68, respectively). FGFR3 mutations, FGFR3::TACC3 fusion events and Hedgehog were strongly enriched in GRI1. GRI3 disease was associated with a germ stem cell-like phenotype and upregulation in APOBEC3B. CONCLUSIONS: WT sequencing data delineated three molecular classes of NMIBC, and improved
Eur Urol Suppl 2017; 16(3);e212
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
128
Molecular tumour grading and classification of non muscle invasive bladder cancer based on whole transcriptome analysis Eur Urol Suppl 2017; 16(3);e213
prediction of disease progression from NMIBC to MI compared to conventional histologic grading. WT analysis could be integrated to a new WHO classification.
Eur Urol Suppl 2017; 16(3);e213 Powered by TCPDF (www.tcpdf.org)
128
Molecular tumour grading and classification of non muscle invasive bladder cancer based on whole transcriptome analysis Eur Urol Suppl 2017; 16(3);e212
Zlotta A.R.1, Shen J.2, Noon A.3, Jiang H.4, Kuk C.1, Ni R.5, Sukhu B.5, Chan K.2, Erlich A.1, Roupret M.6, Seisen T.6, Comparat E.7, Sweet J.8, Kulkarni G.S.9, Fleshner N.E.9, Azad A.5, Van Der Kwast T.H.8, Wrana J.L.2 1
Mount Sinai Hospital, Dept. of Surgery (urology), Toronto, Canada, 2Mount Sinai Hospital, LunenfeldTanenbaum Research Institute, Toronto, Canada, 3University of Sheffield, Dept. of Urology, Sheffield, United Kingdom, 4University Health Network, Dept. of Statistics, Toronto, Canada, 5Mount Sinai Hospital, Dept. of Pathology and Laboratory Medicine, Toronto, Canada, 6Groupe Hospitalier La PitiéSalpêtière, Université Pierre Et Marie Curie, Dept. of Urology, Paris, France, 7Groupe Hospitalier La PitiéSalpêtière, Université Pierre Et Marie Curie, Dept. of Pathology, Paris, France, 8Toronto General Hospital, University Health Network, Dept. of Pathology, Toronto, Canada, 9Princess Margaret Cancer Centre, University Health Network, Dept. of Surgical Oncology, Urology, Toronto, Canada INTRODUCTION & 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. MATERIAL & METHODS: Whole transcriptomic (WT) analysis of 184 bladder tumours (164 NMIBC and 20 MIBC or metastatic) was performed from formalin fixed paraffin embedded (FFPE) tissues incorporating messenger RNA expression, splice variants, gene fusion and mutation detection. In NMIBC, we used a discovery (n=40) and 2 validation cohorts (n= 40 and 84). 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. RESULTS: Unsupervised clustering of data from RNA sequencing revealed classification of three robustnon-overlapping molecular subtypes of NMIBC termed Grade Related Index (GRI) 1, GRI2 and GRI3. GRI1 comprised of almost exclusively LG tumours, while GRI3 clustered with HG MIBC tumours. After assessment by expert pathologists, kappa for interobserver variability in 1973 WHO histological grading was 0.40 whereas it reached 0.78 for the 2004 classification. Most discrepant cases clustered in molecular subtype GRI2. GRI subclassification independently predicted disease progression in NMIBC and outperformed the established risk EORTC calculator (AUC=0.83 vs 0.68, respectively). FGFR3 mutations, FGFR3::TACC3 fusion events and Hedgehog were strongly enriched in GRI1. GRI3 disease was associated with a germ stem cell-like phenotype and upregulation in APOBEC3B. CONCLUSIONS: WT sequencing data delineated three molecular classes of NMIBC, and improved
Eur Urol Suppl 2017; 16(3);e212
32nd Annual EAU Congress, 24-28 March 2017, London, United Kingdom
128
Molecular tumour grading and classification of non muscle invasive bladder cancer based on whole transcriptome analysis Eur Urol Suppl 2017; 16(3);e213
prediction of disease progression from NMIBC to MI compared to conventional histologic grading. WT analysis could be integrated to a new WHO classification.
Eur Urol Suppl 2017; 16(3);e213 Powered by TCPDF (www.tcpdf.org)