The Molecular Characteristics of Upper Tract Urothelial Carcinoma

Upper tract urothelial carcinoma is less common than bladder urothelial carcinoma. The biological characteristics of this form of the disease is not completely understood. A new study published in European Urology by Moss et al. performed an integrated DNA, RNA and protein analysis of upper tract urothelial carcinoma to characterize its molecular landscape.

The study identified a high rate of FGFR3 mutations predominantly in low-grade upper tract urothelial carcinoma. The investigators also identified mutations in KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%) of upper tract urothelial carcinoma. Mutational signatures are specific patterns of mutations pointing to mutagenesis mechanisms. The investigators found that the APOBEC and CpG mutational signatures were the most common in upper tract urothelial carcinoma.

RNA sequencing categorized upper tract urothelial carcinoma into four distinct molecular subtypes. Most notably, tumors belonging to cluster I harbored no PIK3CA mutations, occurred in nonsmokers, high-grade <pT2 tumors and was associated with high recurrences, cluster II and II harbored high rates of FGFR3 mutations and were mostly low-grade tumors. Cluster 3 was enriched in PIK3CA mutations (71%) Cluster IV was enriched in KMT2D (62.5%), FGFR3 (50%) and TP53 (50%) mutations. There were trends towards differences in clinical outcomes between the different molecular clusters but the small sample size precluded statistical significance. The study also identified a novel SH3KBP1-CNTNAP5 genomic rearrangement that potentially regulates RTK signaling.

This study is an important step towards a deeper understanding of the biology of upper tract urothelial carcinoma. Further studies are needed to validate the described subtypes and to define whether these subtypes predict responses to therapy.

Written By: Bishoy Faltas MD

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Reference:
Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma. Moss TJ, Qi Y, Xi L, Peng B, Kim TB, Ezzedine NE, Mosqueda ME, Guo CC, Czerniak BA, Ittmann M, Wheeler DA, Lerner SP, Matin SF.Eur Urol. 2017 Jun 7. pii: S0302-2838(17)30488-8. doi: 10.1016/j.eururo.2017.05.048. [Epub ahead of print]

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