PD18-11 DISTINCT MOLECULAR SUBTYPES AND A HIGH DIAGNOSTIC URINARY BIOMARKER OF UPPER URINARY TRACT UROTHELIAL CARCINOMA

Abstract

INTRODUCTION AND OBJECTIVE: Upper urinary tract urothelial carcinomas (UTUCs) are rare malignancy with histology similar to urothelial bladder carcinomas (UBCs). Compared with UBCs, little is known about the genetic basis of UTUCs, and currently no useful biomarkers are available for them. METHODS: We performed whole exome/RNA sequencing of 209 UTUC samples with various stages. We also conducted targeted sequencing of urinary sediments DNA from 54 UTUC patients (45 pre- and 34 postoperative ones) as well as those from 19 non-urothelial cancer (UC) patients. RESULTS: Hypermutation was observed in 15 samples, of which 12 harbored biallelic mismatch repair genes alterations. Alterations were most frequently observed in TERT promoter (50%), followed by KMT2D (46%), FGFR3 (44%), CDKN2A (44%), and TP53 (36%). Mutually exclusive patterns were observed among alterations in FGFR3, RAS (H-/K-/NRAS), TP53, and MDM2, which covered 93.8% of cases. Analysis of copy number alterations (CNAs) revealed 39.4% of samples had highly complexed karyotype (CK). Based on these genetic features, we established 5 subgroups: hypermutated, FGFR3-mutated, RAS-mutated, TP53-mutated/CK-positive, and triple negative. We found significant association between this classification and clinical outcome, in which tumor phenotype and prognosis were favorable in hypermutated and FGFR3 subtype while those were aggressive in TP53/CK subtype. Expression subtypes identified in clustering analysis of RNA data also showed strong correlation with the mutation subtypes. Interestingly, cluster 3, which was enriched in TP53/CK subtype, showed strong expression of immune markers including druggable targets PDL1 and PDL2.In urinary sediments sequencing, preoperative samples harbored the same mutations and CNAs as their corresponding primary tumors in 84.4% of cases (38/45) regardless of their genotypes or phenotypes, showing significantly higher sensitivity than urine cytology (class 4-5, 31.1%). Tumor-induced severe hydronephrosis were observed in 4 sequencing negative cases. No alterations were detected in all postoperative and non-UC samples (0/34 and 0/19) while 2 non-UC samples showed positive cytology (class4), both of which were diagnosed as benign tumors after surgery. CONCLUSIONS: UTUC showed distinct genetic subtypes characterized by discrete sets of mutations and distinct clinical phenotypes, providing unique therapeutic targets and appropriate treatment strategy. Sequencing urinary sediments is a useful, non-invasive biomarker for precise diagnosis and proper treatment. Source of Funding: Dainippon-Sumitomo Pharmaceutical, Inc. ChordiaTherapeutics, Inc. Kan Research Laboratory, Inc.