Synapse - Molecular heterogeneity and immune infiltration drive clinical outcomes in upper tract urothelial carcinoma

Molecular heterogeneity and immune infiltration drive clinical outcomes in upper tract urothelial carcinoma Journal Article

Authors:	Kim, K.; Alam, S. M.; Kuo, F.; Chen, Z.; Yip, W.; Katims, A. B.; Chu, C.; Lenis, A. T.; Hu, W.; Gokturk Ozcan, G.; Chen, J. F.; Firouzi, S.; Elhanati, Y.; Clinton, T. N.; Aulitzky, A.; Almassi, N.; Fujii, Y.; Tracey, A. T.; Reisz, P. A.; Budhu, S.; Vuong, L.; Eichholz, J.; Woo, H. J.; Nogueira, L.; Gao, S. P.; Scherz, A.; Aggen, D. H.; Rosenberg, J. E.; Pietzak, E. J.; Seshan, V.; Greenbaum, B.; Becker, A.; Akin, O.; Iyer, G.; Al-Ahmadie, H.; Hakimi, A. A.; Merghoub, T.; Solit, D. B.; Coleman, J. A.
Article Title:	Molecular heterogeneity and immune infiltration drive clinical outcomes in upper tract urothelial carcinoma
Abstract:	Background and objective: Molecular classification of upper tract urothelial carcinoma (UTUC) can provide insight into divergent clinical outcomes and provide a biological rationale for clinical decision-making. As such, we performed multi-omic analysis of UTUC tumors to identify molecular features associated with disease recurrence and response to immune checkpoint blockade (ICB). Methods: Targeted DNA and whole transcriptome RNA sequencing was performed on 100 UTUC tumors collected from patients undergoing nephroureterectomy. Consensus non-negative matrix factorization was used to identify molecular clusters associated with clinical outcomes. Gene set enrichment and immune deconvolution analyses were performed. Weighted gene co-expression network analysis was employed for unsupervised identification of gene networks in each cluster. Key findings and limitations: Five molecular clusters with distinct clinical outcomes were identified. Favorable subtypes (C1 and C2) were characterized by a luminal-like signature and an immunologically depleted tumor microenvironment (TME). Subtype C3 was characterized by FGFR3 alterations and a higher tumor mutational burden, and included all tumors with microsatellite instability. Despite higher rates of recurrence and inferior survival, subtypes C4 and C5 harbored an immunologically rich TME favoring response to ICB. Limitations include extrapolation of molecular features of tumors from the primary site to determine response to systemic immunotherapy and the limited resolution of bulk sequencing to distinguish gene expression in the tumor, stroma, and immune compartments. Conclusions and clinical implications: RNA sequencing identified previously underappreciated UTUC molecular heterogeneity and suggests that UTUC patients at the highest risk of metastatic recurrence following surgery include those most likely to benefit from perioperative ICB. © 2024 The Authors
Keywords:	cancer survival; gene cluster; major clinical study; overall survival; clinical feature; cancer recurrence; disease free survival; nuclear magnetic resonance imaging; cd8 antigen; cd8+ t lymphocyte; stat3 protein; progression free survival; computer assisted tomography; gene expression; cell infiltration; cohort analysis; transcriptomics; fibroblast growth factor receptor 3; protein p53; cause of death; dna; gamma interferon; janus kinase; cancer specific survival; microsatellite instability; nephroureterectomy; interleukin 6; eosin; hematoxylin; cytotoxic t lymphocyte antigen 4; transitional cell carcinoma; transcriptome; immunocompetent cell; genetic heterogeneity; programmed death 1 ligand 1; programmed death 1 receptor; tumor microenvironment; copy number variation; clinical outcome; lymphocyte activation gene 3 protein; demographics; immune checkpoint blockade; immune checkpoint inhibitor; immunological parameters; human; male; female; article; rna sequencing; differential expression analysis; gene set enrichment analysis; hepatitis a virus cellular receptor 2; tumor mutational burden; multiomics; non-negative matrix factorization; upper tract urothelial cancer; weighted gene co expression network analysis; molecular clusters; targeted exome sequencing; whole transcriptomic sequencing
Journal Title:	European Urology
Volume:	87
Issue:	3
ISSN:	0302-2838
Publisher:	Elsevier Science, Inc.
Date Published:	2025-03-01
Start Page:	342
End Page:	354
Language:	English
DOI:	10.1016/j.eururo.2024.10.024
PUBMED:	39550333
PROVIDER:	scopus
PMCID:	PMC12092068
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85209152285&doi=10.1016%2fj.eururo.2024.10.024&partnerID=40&md5=00bfd5fac79ad2bfa82fb1a7a62068c1
Notes:	Article -- Source: Scopus