Molecular Alterations in Urothelial Carcinoma Using CLIA-certified Genomic Testing - Expert Commentary

Defining the genomic landscapes that characterize the different disease states of urothelial carcinoma is an important area of investigation. A recent study by Nassar et al. recently published in Clinical Cancer Research characterized the molecular changes across the clinical spectrum of urothelial carcinoma (UC).

The investigators used a CLIA-certified targeted exome sequencing panel of 237 genes to examine UC tumors across the full spectrum of grade, stage, and anatomical locations. The investigators profiled 82 low-grade non-muscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC tumors. Interestingly, the investigators identified that FGFR3 and KDM6A mutations were significantly enriched in LG-NMIBC (72% and 44%, respectively) versus other bladder cancer subtypes. 

Similar to previous reports showing the KDM6A is a sexually dimorphic gene, the investigators found that women with LG-NMIBC tumors had a significantly higher frequency of KDM6A mutations than men (10 of 14, 71% versus 26 of 68, 38%, p<0.05. TP53 and RB1 mutations were significantly enriched in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%-58% vs. 4%; 9%-22% vs. 0; respectively) supporting their role in more advanced disease. The study also identified a higher tumor mutational burden and an enrichment of APOBEC mutational signature in HG-NMIBC and MIBC tumors compared with LG-NMIBC and HG-UTUC.

The study sheds light on the subtle but important differences between the mutational profiles of different urothelial cancer disease states. The next step towards translation would be to learn how to leverage these differences for adaptive therapeutic strategies for each urothelial cancer disease state.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

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1. Nassar AH, Umeton R, Kim J, Lundgren K, Harshman L, Van Allen EM, Preston M, Dong F, Bellmunt J, Mouw KW, Choueiri TK, Sonpavde G, Kwiatkowski DJ. Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites. Clin Cancer Res. 2019 Apr 15;25(8):2458-2470. doi: 10.1158/1078-0432.CCR-18-3147. Epub 2018 Dec 28
2. Kaneko S1, Li X1.X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci Adv. 2018 Jun 13;4(6):eaar5598. doi: 10.1126/sciadv.aar5598. eCollection 2018 Jun.
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