| 1. |
- Hedegaard, Jakob, et al.
(författare)
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Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
- 2016
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 30:1, s. 27-42
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Tidskriftsartikel (refereegranskat)abstract
- Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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| 2. |
- Sjödahl, Gottfrid, et al.
(författare)
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Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases
- 2018
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 31:12, s. 1869-1881
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Tidskriftsartikel (refereegranskat)abstract
- Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle-invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28 matched lymph-node metastases. Full section immunohistochemistry was performed to assess intra-tumor subtype heterogeneity in discordant cases, and exome sequencing was performed for 20 sample pairs. Discordant subtype classification between the bladder tumor and lymph-node metastasis was generally rare (12/67, 18%), but most (7/12, 58%) involved the Basal/Squamous-like subtype. Discordant Basal/Squamous-like tumors showed either Urothelial-like or Genomically Unstable, luminal-like phenotype in the lymph-node metastasis. Full section immunohistochemistry revealed intra-tumor subtype heterogeneity for six discordant cases including four involving the Basal/Squamous-like subtype. Subtype concordance for non- Basal/Squamous-like tumors was 91%. RNA-based classification agreed with immunohistochemistry classification but quantitative assessment is necessary to avoid false detection of subtype shifts. Most high confidence cancer mutations were shared between samples (n = 93, 78%), and bladder tumor private mutations (n = 20, 17%) were more frequent than those private to the lymph-node metastasis (n = 7, 6%). We conclude that bladder tumors and lymph-node metastases have overall similar molecular subtype, biomarker expression, and cancer mutations. The main exception was tumors of the Basal/Squamous-like subtype where most cases showed discordant classification, some with evidence of intra-tumor heterogeneity. The data are of relevance for neoadjuvant treatment stratification and raises questions on the dynamics of molecular subtypes during bladder cancer progression.
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| 3. |
- Viborg Lindskrog, Sia, et al.
(författare)
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An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.
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