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Genomics of bladder cancer and novel molecular taxonomy.pptx

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Sudipta Naskar
Sudipta Naskar

Bladder cancers exhibit complex genotype with significant intratumoral heterogeneity. Molecular classification can provide insight to the more precise and individualized therapeutic approach

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GENOMICS OF BLADDER CANCER AND NOVEL MOLECULAR TAXONOMY DR. SUDIPTA NASKAR, TUMOR PATHOLOGY FELLOW SSCHRC
MIBC vs NMIBC
Importance of molecular taxonomy Diverse molecular alteration are responsible for the heterogenity of the disease Extremely heterogeneous genetic profile because of the high mutational rates. Respond will be better when targeted therapy is focused on the main impaired pathway. Can provide new insights for defining prognosis and planning treatment options particularly for MIBC
Identify the set of patients who can safely avoid neoadjuvant chemotherapy. Targeted therapy can be provided according to the subtype
Studies describing the molecular subtypes 1. Lund university 2. TCGA 3. University of North Carolina 4. Texas (MD Anderson) Most comprehensive the Lund University group and that of the TCGA.
Genomics of bladder cancer and novel molecular taxonomy.pptx
Genomics of bladder cancer and novel molecular taxonomy.pptx
FGFR3 Chr 9 Tp53, CDKN2A, RAS, MDM2, PTEN, EGFR
Initial classification by the LUND university group MS1 LOW GRADE (Ta) MS2 HIGHER GRADE AND STAGE [>=T2] FGFR3 gene mutation signature Genome-wide gene expression analysis of 144 tumors, including both muscle-invasive and nonmuscle invasive bladder tumors.
The LUND University Classification Urobasal A KRT5 and FGFR3 overexpression Genomically unstable TP53 mutations & ERBB2 overexpression SCC Like overexpression of basal keratins Urobasal B LOW GRADE Infiltrating type HIGH GRADE, Tp53 like signature Favourable Prognosis MIBC Poor prognosis
Genomics of bladder cancer and novel molecular taxonomy.pptx
KRT14 KRT5 EGFR ERBB2 KRT14 KRT5 EGFR ERBB2 UROBASAL A UROBASAL B CCND1 FGFR3 CCND1 FGFR3 TP63 DSC 2/3 TP63 DSC 2/3 E-Cad P-Cad E-Cad P-Cad CCNB1 MKI67 CCNB1 MKI67
Genomics of bladder cancer and novel molecular taxonomy.pptx
Addition to original LUND classification Mesenchymal like subtype High expression of Vimentin, ZEB2 Small cell/neuroendocrine- like TP53 mutations & ERBB2 overexpression Low expression of FOXA1, GATA3, KRT5, and KRT14. Chromogranin, synaptophysin, NSE, and NCAM1
The TCGA Classification
The TCGA Cluster summary Papillary histology FGFR3-related miRNA expression FGFR3 expression and reduced FGFR3 alterations Cluster 1 Luminal (Breast Like) Enriched in urothelial differentiation factors UPK, GATA3, ERBB2 mutation/ amp Cluster 2 BASAL / SCC Like KRT5, KRT6A, KRT14, EGFR overexpression Cluster 3 Not otherwise specified Cluster 4
THE UNC CLASSIFICATION
Use of BASE47 gene signature to classify HGUCs two molecular subtypes of high-grade UC LUMINAL expression of terminal urothelial differentiation markers, such as those seen in umbrella cells (UPK1B, UPK2, UPK3A, and KRT20). BASAL High levels of genes that typically mark urothelial basal cells (KRT14, KRT5, and KRT6B). They found similarities between Luminal and Basal subtypes of breast cance. Dissimilarities as well Claudin-low bladder tumors are a subpopulation of the basal-like bladder cancers claudin low subtypes in breast can arise from multiple intrinsic subtype.
Genomics of bladder cancer and novel molecular taxonomy.pptx
Consensus classification Aure卒lie Kamoun, Aure卒lien de Reynie`s, Yves Allory, Gottfrid Sjo即dahl, A. Gordon Robertson, Roland Seiler et al (2020) Used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. Built a weighted network of subtyping results, using Cohens kappa metric Quantified similarities between subtypes from different classification systems Formed Markov cluster algorithm to identify robust network substructures corresponding to potential consensus classes
Markov cluster Network
Consensus Classes 1. Luminal papillary (LumP) >50% of these tumors activate FGFR3 through either mutation, fusion, or genomic amplification. 2. Luminal Non-Specified (LumNS) 1. Only 8% of the 1750 MIBC tumors analyzed. 2. enriched with micropapillary histological variants, and is 3. significantly associated with carcinoma in situ 3. Luminal Unstable (LumU) Refers to the genomically unstable class name in the Lund molecular taxonomy, LumU tumors display several features of genomic instability higher overall and APOBEC mutation burdens, and more somatic copy number alterations. 4. Basal/Squamous (Ba/Sq) notably high levels of KRT14, KRT5/6, and a lack of GATA3 and FOXA1
5. Stroma-rich It includes both luminal and non-luminal tumors reflects the microenvironment, strongly overlapping with Infiltrated subtypes from TCGA and Lund classifications 6. Neuroendocrine-like (NE-like) This consensus class is strongly associated with neuroendocrine histological variants associated with TCGA Neuronal subtype
Genomics of bladder cancer and novel molecular taxonomy.pptx
Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis 1. GATA3+ or KRT20+ expression 2. Rarely GATA3+ & KRT20+/KRT14 low/KRT5 low cases KRT14+ or KRT5+ or GATA3 low/- or KRT20 low/- KRT14-/KRT5-/GATA3- /KRT20- luminal null/double-negative (non-luminal/non-basal) Basaal
A c c o r d i n g t o p a t h o l o g i c t u m o r c l a s s i f i c a t i o n ( C o n v e n t i o n a l V S . Va r i a n t h i s t o l o g y u r o t h e l i a l c a r c i n o m a ) The KaplanMeier plots
Genomics of bladder cancer and novel molecular taxonomy.pptx
Management strategy according to the molecular subtypes
NMIBC molecular classification First comprehensive study was done at Aarhus University Hospital, Denmark in 2016 Sub-grouped into three major classes with basal- and luminal- like characteristics Class 1, Class 2, Class 3. Class 3 tumors elevated levels of lncRNA expression, decreased expression of protein-encoding genes, and reduced isoform switching. APOBEC-related mutational signature based on RNA-seq data preferentially in the class 2 patient group with poor prognosis.
Class 1 tumors high expression of early cell-cycle genes Class 2 tumors high expression of late cell-cycle genes Class 3 tumors Expression of basal like markers like CD44, CK5, CK15 Uroplakin, BAMBI, PPARG, SPINK
Genomics of bladder cancer and novel molecular taxonomy.pptx
Normal urothelium CIS pathway Class 1 Class 3 Ta pathway Schematic Pathway of NMIBC MIBC Class 2 Class shift MIBC
NBMIC genomics Luminal-like Differentiation Basal-like EMT TF activity CSC activity Cell cycle activity Molecular signature Mutations Class 1 UPKs, PPARG, GRHL3, BAMBI, SPINK1 Early: CCND1 ID1 RBL2 FGFR3 Class 3 GATA3 UPKs, PPARG, KRT20, GRHL3, BAMBI, SPINK1 FGFR3 RNA-editing signature Class 2 UPKs, PPARG, KRT20, GRHL3, BAMBI, SPINK1 Keratin14 SOX9, TWIST1, FOXF1, ZEB1, ZEB2, GATA6 PROM1, ALDH1A1, ALDH1A2, ALDH1A3, NES, THY Late: CDC20 CDC25A CDKs PLK1 CIS+ Prog.+ TP53 ERCC2 APOBEC mutation signature
MOLECULAR UPDATES IN SPECIFIC VARIANTS OF UROTHELIAL CARCINOMA
MICROPAPILLARY UROTH ELIAL CARCINOMA Rare and aggressive variant. Small tight clusters of highgrade tumor cells lacking true fibrovascular cores and present within lacunar spaces. Strong association with ERBB2 gene amplification and HER2 overexpression.
Genomics of bladder cancer and novel molecular taxonomy.pptx
PLASMACYTOID UROTHELIAL CARCINOMA Rare and aggressive variant of bladder cancer. Discohesive and infiltrating growth. Truncating CDH1 mutations or promoter hypermethylation --> Loss of E-cadherin expression. No association with CDH1 germline mutations. Genomic background otherwise similar to urothelial carcinoma.
Divergent evolution of plasmacytoid and urothelial NOS components within a tumor with distinct histologic regions CDKN1A PIK3C2G PHOX2B InDels PGDFRA G829E EGFR amp MDM2 amp CDH1 alterations Truncated Mutations
SMALL CELL / NEUROENDOCRINECARCINO MA OF THE BLADDER Rare and aggressive variant of bladder cancer. Similar to small cell carcinoma in other organs. Strong association with TP53/RB1 co- alterations. Genetic background similar to bladder cancer and strongly associated with APOBEC signature.
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Genomics of bladder cancer and novel molecular taxonomy.pptx

  • 1. GENOMICS OF BLADDER CANCER AND NOVEL MOLECULAR TAXONOMY DR. SUDIPTA NASKAR, TUMOR PATHOLOGY FELLOW SSCHRC
  • 3. Importance of molecular taxonomy Diverse molecular alteration are responsible for the heterogenity of the disease Extremely heterogeneous genetic profile because of the high mutational rates. Respond will be better when targeted therapy is focused on the main impaired pathway. Can provide new insights for defining prognosis and planning treatment options particularly for MIBC
  • 4. Identify the set of patients who can safely avoid neoadjuvant chemotherapy. Targeted therapy can be provided according to the subtype
  • 5. Studies describing the molecular subtypes 1. Lund university 2. TCGA 3. University of North Carolina 4. Texas (MD Anderson) Most comprehensive the Lund University group and that of the TCGA.
  • 8. FGFR3 Chr 9 Tp53, CDKN2A, RAS, MDM2, PTEN, EGFR
  • 9. Initial classification by the LUND university group MS1 LOW GRADE (Ta) MS2 HIGHER GRADE AND STAGE [>=T2] FGFR3 gene mutation signature Genome-wide gene expression analysis of 144 tumors, including both muscle-invasive and nonmuscle invasive bladder tumors.
  • 10. The LUND University Classification Urobasal A KRT5 and FGFR3 overexpression Genomically unstable TP53 mutations & ERBB2 overexpression SCC Like overexpression of basal keratins Urobasal B LOW GRADE Infiltrating type HIGH GRADE, Tp53 like signature Favourable Prognosis MIBC Poor prognosis
  • 12. KRT14 KRT5 EGFR ERBB2 KRT14 KRT5 EGFR ERBB2 UROBASAL A UROBASAL B CCND1 FGFR3 CCND1 FGFR3 TP63 DSC 2/3 TP63 DSC 2/3 E-Cad P-Cad E-Cad P-Cad CCNB1 MKI67 CCNB1 MKI67
  • 14. Addition to original LUND classification Mesenchymal like subtype High expression of Vimentin, ZEB2 Small cell/neuroendocrine- like TP53 mutations & ERBB2 overexpression Low expression of FOXA1, GATA3, KRT5, and KRT14. Chromogranin, synaptophysin, NSE, and NCAM1
  • 16. The TCGA Cluster summary Papillary histology FGFR3-related miRNA expression FGFR3 expression and reduced FGFR3 alterations Cluster 1 Luminal (Breast Like) Enriched in urothelial differentiation factors UPK, GATA3, ERBB2 mutation/ amp Cluster 2 BASAL / SCC Like KRT5, KRT6A, KRT14, EGFR overexpression Cluster 3 Not otherwise specified Cluster 4
  • 18. Use of BASE47 gene signature to classify HGUCs two molecular subtypes of high-grade UC LUMINAL expression of terminal urothelial differentiation markers, such as those seen in umbrella cells (UPK1B, UPK2, UPK3A, and KRT20). BASAL High levels of genes that typically mark urothelial basal cells (KRT14, KRT5, and KRT6B). They found similarities between Luminal and Basal subtypes of breast cance. Dissimilarities as well Claudin-low bladder tumors are a subpopulation of the basal-like bladder cancers claudin low subtypes in breast can arise from multiple intrinsic subtype.
  • 20. Consensus classification Aure卒lie Kamoun, Aure卒lien de Reynie`s, Yves Allory, Gottfrid Sjo即dahl, A. Gordon Robertson, Roland Seiler et al (2020) Used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts. Built a weighted network of subtyping results, using Cohens kappa metric Quantified similarities between subtypes from different classification systems Formed Markov cluster algorithm to identify robust network substructures corresponding to potential consensus classes
  • 22. Consensus Classes 1. Luminal papillary (LumP) >50% of these tumors activate FGFR3 through either mutation, fusion, or genomic amplification. 2. Luminal Non-Specified (LumNS) 1. Only 8% of the 1750 MIBC tumors analyzed. 2. enriched with micropapillary histological variants, and is 3. significantly associated with carcinoma in situ 3. Luminal Unstable (LumU) Refers to the genomically unstable class name in the Lund molecular taxonomy, LumU tumors display several features of genomic instability higher overall and APOBEC mutation burdens, and more somatic copy number alterations. 4. Basal/Squamous (Ba/Sq) notably high levels of KRT14, KRT5/6, and a lack of GATA3 and FOXA1
  • 23. 5. Stroma-rich It includes both luminal and non-luminal tumors reflects the microenvironment, strongly overlapping with Infiltrated subtypes from TCGA and Lund classifications 6. Neuroendocrine-like (NE-like) This consensus class is strongly associated with neuroendocrine histological variants associated with TCGA Neuronal subtype
  • 25. Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis 1. GATA3+ or KRT20+ expression 2. Rarely GATA3+ & KRT20+/KRT14 low/KRT5 low cases KRT14+ or KRT5+ or GATA3 low/- or KRT20 low/- KRT14-/KRT5-/GATA3- /KRT20- luminal null/double-negative (non-luminal/non-basal) Basaal
  • 26. A c c o r d i n g t o p a t h o l o g i c t u m o r c l a s s i f i c a t i o n ( C o n v e n t i o n a l V S . Va r i a n t h i s t o l o g y u r o t h e l i a l c a r c i n o m a ) The KaplanMeier plots
  • 28. Management strategy according to the molecular subtypes
  • 29. NMIBC molecular classification First comprehensive study was done at Aarhus University Hospital, Denmark in 2016 Sub-grouped into three major classes with basal- and luminal- like characteristics Class 1, Class 2, Class 3. Class 3 tumors elevated levels of lncRNA expression, decreased expression of protein-encoding genes, and reduced isoform switching. APOBEC-related mutational signature based on RNA-seq data preferentially in the class 2 patient group with poor prognosis.
  • 30. Class 1 tumors high expression of early cell-cycle genes Class 2 tumors high expression of late cell-cycle genes Class 3 tumors Expression of basal like markers like CD44, CK5, CK15 Uroplakin, BAMBI, PPARG, SPINK
  • 32. Normal urothelium CIS pathway Class 1 Class 3 Ta pathway Schematic Pathway of NMIBC MIBC Class 2 Class shift MIBC
  • 33. NBMIC genomics Luminal-like Differentiation Basal-like EMT TF activity CSC activity Cell cycle activity Molecular signature Mutations Class 1 UPKs, PPARG, GRHL3, BAMBI, SPINK1 Early: CCND1 ID1 RBL2 FGFR3 Class 3 GATA3 UPKs, PPARG, KRT20, GRHL3, BAMBI, SPINK1 FGFR3 RNA-editing signature Class 2 UPKs, PPARG, KRT20, GRHL3, BAMBI, SPINK1 Keratin14 SOX9, TWIST1, FOXF1, ZEB1, ZEB2, GATA6 PROM1, ALDH1A1, ALDH1A2, ALDH1A3, NES, THY Late: CDC20 CDC25A CDKs PLK1 CIS+ Prog.+ TP53 ERCC2 APOBEC mutation signature
  • 34. MOLECULAR UPDATES IN SPECIFIC VARIANTS OF UROTHELIAL CARCINOMA
  • 35. MICROPAPILLARY UROTH ELIAL CARCINOMA Rare and aggressive variant. Small tight clusters of highgrade tumor cells lacking true fibrovascular cores and present within lacunar spaces. Strong association with ERBB2 gene amplification and HER2 overexpression.
  • 37. PLASMACYTOID UROTHELIAL CARCINOMA Rare and aggressive variant of bladder cancer. Discohesive and infiltrating growth. Truncating CDH1 mutations or promoter hypermethylation --> Loss of E-cadherin expression. No association with CDH1 germline mutations. Genomic background otherwise similar to urothelial carcinoma.
  • 38. Divergent evolution of plasmacytoid and urothelial NOS components within a tumor with distinct histologic regions CDKN1A PIK3C2G PHOX2B InDels PGDFRA G829E EGFR amp MDM2 amp CDH1 alterations Truncated Mutations
  • 39. SMALL CELL / NEUROENDOCRINECARCINO MA OF THE BLADDER Rare and aggressive variant of bladder cancer. Similar to small cell carcinoma in other organs. Strong association with TP53/RB1 co- alterations. Genetic background similar to bladder cancer and strongly associated with APOBEC signature.

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