(UroToday.com) The 2023 American Urological Association (AUA) annual meeting held in Chicago, IL was host to an upper tract transitional cell carcinoma podium session. Dr. Paul Yonover presented the results of a case-control study evaluating urinary comprehensive genomic profiling aids in the detection and risk prognosis of upper tract urothelial carcinoma.
Upper tract urothelial carcinoma (UTUC) remains challenging to diagnose and treat, with current diagnostic modalities having significant limitations and patients often requiring repeat upper tract instrumentation and contrast-enhanced imaging for surveillance purposes. A urine test capable of detecting UTUC and that provides diagnostic and prognostic information might aid diagnosis and improve risk stratification, which remain major clinical challenges in UTUC.
Urinary comprehensive genomic profiling (uCGP) via next-generation sequencing with the CLIA-validated UroAmp assay (Convergent Genomics) was developed to identify mutations, diagnose disease, assess molecular grade and stage, and predict recurrence risk. In this study, the investigators sought to evaluate the performance of UroAmp in UTUC patients and to identify unique genomic patterns in both UTUC and urothelial carcinoma of the bladder.
uCGP with the UroAmp test was performed on 69 specimens from individuals with de novo pathology-confirmed UC of the bladder (UCB) and 12 urine specimens from individuals with de novo pathologically-confirmed UTUC. Urine DNA was sequenced, comprehensively profiled across 60 genes, and disease classification was predicted via a machine learned algorithm. Differential mutational signals of UTUC and UCB were compared via an odds ratio with statistical significance evaluated via Fisher’s exact test.
Among UTUC patients, 83% had high-grade disease, compared to 17% with low-grade. The stage distribution is summarized below, with 50% of patients having Ta or T1 disease, and 8% (1 patient) each having T3-T4 disease.
At a UroAmp score cutoff of 50%, uCGP correctly classified 100% of UTUC subjects and 97% (67/69) of UCB subjects as disease positive.
UTUC lesions had a high prevalence of TP53 mutations (70%) and frequently demonstrated genomic instability with large scale aneuploidy (40%), loss of heterozygosity (30%), ERCC2 amplification (30%), and CDKN2A loss (10%). Additional recurrent mutations included:
- KMT2C (40%)
- KMT2D (40%)
- FGFR3 (30%)
- TERT (30%).
Univariable analysis revealed significant enrichment of promoter mutations in TERT (OR=10.6) among high grade UCB lesions compared to high grade UTUC. Further, mutations in ARID1A, PLEKHS1, were solely observed in high grade UCB lesions.
The authors concluded that uCGP with UroAmp is a quantitative diagnostic tool with the ability to profile genomic lesions in UTUC and UCB. While further studies are needed, distinct mutational patterns in UTUC could potentially serve to identify urologic origins of urine-based disease signals.
Presented by: Paul M. Yonover, MD, FACS, Clinical Assistant Professor of Urology, University of Illinois at Chicago College of Medicine, Chicago, IL
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023