Mutational Analysis Reveals the Relationship Between Upper Tract and Lower Tract Urothelial Carcinomas - Expert Commentary

Although urothelial carcinomas of the bladder and upper tract urothelial carcinoma (UTUC) can have similar histology, they significantly differ in prevalence and risk factors. A recent paper published by Audenet et al. in Clinical Cancer Research explored the genetic relatedness between UTUC and urothelial carcinomas of the bladder. The cohort included 195 UTUC patients and 454 urothelial carcinomas of the bladder patients with no prior history of UTUC. The investigators analyzed matched tumor and germ-line DNA by using targeted NGS platform (MSK-IMPACT). 

FGFR3 (40%), KMT2D (37%), KDM6A (32%), TP53 (26%) and ARID1A (23%) were the most frequently mutated genes in UTUC. Interestingly, only a minority  (6.2%) of UTUC tumors and (1.1%) of urothelial carcinomas of the bladder tumors were classified as MSI-high (MSIsensor score ≥10). Germ-line sequencing was performed on 47 out of the 195 UTUC patients revealing that 12 of these 47 patients had a pathogenic or likely pathogenic mutation in a Lynch syndrome-associated genes. Tumors from these patients had a high tumor mutational burden (range 22 to 472, median: 54.9, IQR: 32.4-67.0) but only 10 had an MSI sensor score of ≥10. 

Interestingly, the clonal analysis of lower tract recurrences in UTUC patients showed that all pairs of UTUC and recurrent urothelial carcinomas of the bladder were clonal (P<0.005). This important study sheds light on the mutational profiles of UTUC tumors. The close clonal relationship between UTUC and urothelial carcinomas of the bladder tumors support the “drop metastases” theory. Future studies dissecting the transcriptomic, epigenetic, immune landscapes of the UTUC phenotype are needed. 


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

Abstract Reference: 
Audenet F. et al. Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma. Clin Cancer Res. 2018 Oct 23. pii: clincanres.2039.2018. doi: 10.1158/1078-0432.CCR-18-2039.


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