Stratification of cancer into biologically and molecularly similar subgroups is a cornerstone of precision medicine. The Lund Taxonomy classification system for urothelial carcinoma aims to be applicable across the whole disease spectrum including both non-muscle-invasive and invasive bladder cancer. A successful classification system is one that can be robustly and reproducibly applied to new samples.
View Article and Find Full Text PDFBladder cancer is a heterogenous disease, and molecular subtyping is a promising method to capture this variability. Currently, the immune compartment in relation to subtypes is poorly characterized. Here, we analyzed the immune compartment in bladder tumors and normal bladder urothelium with a focus on T cell subpopulations using flow cytometry and RNA sequencing.
View Article and Find Full Text PDFUrothelial cancer of the urinary bladder frequently metastasizes to lymph-nodes, lungs, liver and bone. A taxonomy for molecular classification exists, but it is unknown if molecular subtypes show tropism for different organs. Here, we study 146 patients with de novo metastatic disease or recurrence after curative treatment.
View Article and Find Full Text PDFUnlabelled: The current diagnostic pathway for patients with muscle-invasive bladder cancer (MIBC), which involves with computed tomography urography, cystoscopy, and transurethral resection of the bladder (TURB) to histologically confirm MIBC, delays definitive treatment. The Vesical Imaging-Reporting and Data System (VI-RADS) has been suggested for MIBC identification using magnetic resonance imaging (MRI), but a recent randomized trial reported misclassification in one-third of patients. We investigated a new endoscopic biopsy device (Urodrill) for histological confirmation of MIBC and assessment of molecular subtype by gene expression in patients with VI-RADS 4 and 5 lesions on MRI.
View Article and Find Full Text PDFStudies to date on biomarkers predictive of response to bacillus Calmette-Guérin (BCG) treatment for non-muscle-invasive bladder cancer have only identified markers with prognostic potential. There is an urgent need for larger study cohorts and for control arms comprising BCG-untreated patients to identify biomarkers with true ability to predict BCG response in classifying this patient population.
View Article and Find Full Text PDFTreatment of bladder cancer patients depends on precise diagnosis. Molecular subtyping by gene expression profiling may contribute substantially to subclassification of bladder cancer. Several classification systems have been proposed.
View Article and Find Full Text PDFBackground: Bladder cancer is molecularly one of the most heterogenous malignancies characterized by equally heterogenous clinical outcomes. Standard morphological assessment with pathology and added immunohistochemical analyses is unable to fully address the heterogeneity, but up to now treatment decisions have been made based on such information only. Bladder cancer molecular subtypes will likely provide means for a more personalized bladder cancer care.
View Article and Find Full Text PDFInterferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory "checkpoint" receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines.
View Article and Find Full Text PDFThe precise classification of tumors into relevant molecular subtypes will facilitate both future research and optimal treatment. Here, the Lund Taxonomy system for molecular classification of urothelial carcinoma was applied to two large and independent cohorts of non-muscle-invasive tumors. Of 752 tumors classified, close to 100% were of the luminal subtypes, 95% urothelial-like (Uro; UroA, UroB, or UroC) and 5% genomically unstable.
View Article and Find Full Text PDFBladder cancer is a common and highly heterogeneous malignancy with a relatively poor outcome. Patient-derived tumor organoid cultures have emerged as a preclinical model with improved biomimicity. However, the impact of the different methods being used in the composition and dynamics of the models remains unknown.
View Article and Find Full Text PDFThere are no established biomarkers to guide patient selection for neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer. Recent studies suggest that molecular subtype classification holds promise for predicting chemotherapy response and/or survival benefit in this setting. Here, we summarize and discuss the scientific literature examining transcriptomic or panel-based molecular subtyping applied to neoadjuvant chemotherapy-treated patient cohorts.
View Article and Find Full Text PDFSeveral groups have during past years produced molecular classification schemes for bladder cancer. Even though no consensus on how to define a subtype exists, one approach has been to base definitions on how tumours cluster according to their mRNA expression profiles. In many cases, obtained profiles, and thus class defining features, are affected by signals from non-tumour cells within the biopsy.
View Article and Find Full Text PDFUnderstanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion.
View Article and Find Full Text PDFMotivation: Gene expression-based multiclass prediction, such as tumor subtyping, is a non-trivial bioinformatic problem. Most classifier methods operate by comparing expression levels relative to other samples. Methods that base predictions on the expression pattern within a sample have been proposed as an alternative.
View Article and Find Full Text PDFBackground: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.
Objective: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.
Design, Setting, And Participants: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining.
Bioinformatics
September 2021
Motivation: k-Top Scoring Pairs (kTSP) algorithms utilize in-sample gene expression feature pair rules for class prediction, and have demonstrated excellent performance and robustness. The available packages and tools primarily focus on binary prediction (i.e.
View Article and Find Full Text PDFWe used the fact that patients with non-muscle invasive bladder tumors show local recurrences and multiple tumors to study re-initiation of tumor growth from the same urothelium. By extensive genomic analyses we show that tumors from the same patient are clonal. We show that gross genomic chromosomal aberrations may be detected in one tumor, only to be undetected in a recurrent tumor.
View Article and Find Full Text PDFMolecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression.
View Article and Find Full Text PDFBackground: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.
Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.