Summary We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival ‘neuronal’ subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, lncRNA, and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma-in-situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.
The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.
, and the Upper TractUrothelial Carcinoma Collaboration BACKGROUND: The literature on upper tract urothelial carcinoma (UTUC) has been limited to small, single center studies. A large series of patients treated with radical nephroureterectomy for UTUC were studied,
Preparation for biopsy should include antimicrobial prophylaxis and pain management. Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention. Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.
Bladder cancer is a highly prevalent disease and is associated with substantial morbidity, mortality and cost. Environmental or occupational exposures to carcinogens, especially tobacco, are the main risk factors for bladder cancer. Most bladder cancers are diagnosed after patients present with macroscopic haematuria, and cases are confirmed after transurethral resection of bladder tumour (TURBT), which also serves as the first stage of treatment. Bladder cancer develops via two distinct pathways, giving rise to non-muscle-invasive papillary tumours and non-papillary (solid) muscle-invasive tumours. The two subtypes have unique pathological features and different molecular characteristics. Indeed, The Cancer Genome Atlas project identified genetic drivers of muscle-invasive bladder cancer (MIBC) as well as subtypes of MIBC with distinct characteristics and therapeutic responses. For non-muscle-invasive bladder cancer (NMIBC), intravesical therapies (primarily Bacillus Calmette-Guérin (BCG)) with maintenance are the main treatments to prevent recurrence and progression after initial TURBT; additional therapies are needed for those who do not respond to BCG. For localized MIBC, optimizing care and reducing morbidity following cystectomy are important goals. In metastatic disease, advances in our genetic understanding of bladder cancer and in immunotherapy are being translated into new therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.