Genomic analysis of same-patient metachronous upper-tract and bladder urothelial carcinoma.

Abstract

449 Background: Despite similarities between upper-tract (UTUC) and bladder urothelial carcinoma (BUC), distinctive clinicopathologic and genomic differences are being described. We further investigate the genomic landscape of these two interrelated malignancies in same-patient metachronous (m) UTUC and BUC using next generation sequencing (NGS). Methods: Following institutional board approval, UTUC and BUC samples were obtained from patients via surgical resection or endoscopic biopsy. Tumors were macrodissected from unstained formalin-fixed, paraffin-embedded slides. Study inclusion was untreated patient samples of UTUC and/or BUC divided into 4 groups: 1) UTUC with mBUC, 2) BUC with mUTUC, 3) Synchronous BUC and UTUC, 4) UTUC with no bladder history. Exclusions were for inadequate clinical data or histological tumor purity < 30%. Whole transcriptome RNA sequencing was performed and analyzed using BASE47 panel (includes basal, luminal, p53-like and cell cycle genes). Results: A total of 95 (UTUC = 61, BUC = 34) samples from 40 patients were analyzed. UTUC samples were 33 primary ureter and 28 renal pelvis cancer. Median age was 72 years, 68% male, 76% Caucasian, 60% former smokers. Groups samples were: 1) UTUC (n = 19), mBUC (n = 12); 2) BUC (n = 12), mUTUC (n = 9); 3) Synchronous UTUC/BUC (n = 10); and 4) UTUC (n = 23). Unsupervised hierarchical clustering segregated tumors into basal-like and luminal subtypes, with 87.5% of metachronous tumors displaying conserved subtype membership. For the groups with UTUC and BUC, only 3/24 (12.5%) clusters (2 patients in Group 2, and 1 patient in Group 3) had unmatched basal/luminal subtypes. Conclusions: NGS analysis of same-patient metachronous UTUC and BUC shows that the majority stay within the same molecular subtype regardless of chronologic development or anatomic origin. Additional studies are necessary to explore differences that may occur within the subtypes, the role of methylation, and clinical correlates.