They noted that TP53 mutations were enriched in metastatic tumors compared to primary sites. APOBEC mutagenesis was detected in a vast majority (91%) of samples and correlated with APOBEC expression. Tumors with high APOBEC mutagenesis had high ploidy, more somatic mutations, and more copy number aberrations.
Based on combined analysis, they defined five clinically relevant molecular subtypes by RNAseq analyses that were distinct in their gene expression, genomic alterations, pathway activity, and immune cell infiltration profiles (Figure). Two subtypes resembled the luminal subtypes identified in primary bladder cancer, and the other subtypes had stroma-rich, basal/squamous, or otherwise unspecific phenotypes. The luminal subtypes were characterized by FGFR3 and PPARG overexpression and may benefit from targeted inhibitors of these markers. The stroma-rich subtype appeared to be PDGFRA-driven, and this may therefore serve as a therapeutic target. The basal/squamous subtype had high levels of CD274, the gene that encodes PD-L1, and checkpoint inhibitors could be effective here.
Figure: Characterizing unique molecular subtypes of metastatic urothelial carcinoma.
This comprehensive genomic analysis provides a unique glimpse into the genomic landscape of metastatic urothelial carcinoma and can serve as a framework for further research on personalizing systemic treatment for these patients.
Presented by: Alberto Nakauma-Gonzalez, PhD, Cancer Computational Biology Center, Erasmus University Medical Center, The Netherlands.
Written by: Anirban P. Mitra, MD, PhD, Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @UroDocAsh at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.