Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

• Published in: Cancer cell Vol. 39; no. 6; pp. 793 - 809.e8
• Main Authors: Fujii, Yoichi, Sato, Yusuke, Suzuki, Hiromichi, Kakiuchi, Nobuyuki, Yoshizato, Tetsuichi, Lenis, Andrew T., Maekawa, Shigekatsu, Yokoyama, Akira, Takeuchi, Yasuhide, Inoue, Yoshikage, Ochi, Yotaro, Shiozawa, Yusuke, Aoki, Kosuke, Yoshida, Kenichi, Kataoka, Keisuke, Nakagawa, Masahiro M., Nannya, Yasuhito, Makishima, Hideki, Miyakawa, Jimpei, Kawai, Taketo, Morikawa, Teppei, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Nagae, Genta, Sanada, Masashi, Sugihara, Eiji, Sato, Taka-Aki, Nakagawa, Tohru, Fukayama, Masashi, Ushiku, Tetsuo, Aburatani, Hiroyuki, Miyano, Satoru, Coleman, Jonathan A., Homma, Yukio, Solit, David B., Kume, Haruki, Ogawa, Seishi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.06.2021
• Subjects: Aged; Biomarkers, Tumor - genetics; Biomarkers, Tumor - urine; Carcinoma, Transitional Cell - diagnosis; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - mortality; DNA Methylation; Female; FGFR3; Gene Dosage; Gene Expression Regulation, Neoplastic; Humans; hypermutation; integrated molecular study; Male; Middle Aged; molecular classification; molecular diagnostic; Mutation; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-mdm2 - genetics; RAS; ras Proteins - genetics; Receptor, Fibroblast Growth Factor, Type 3 - genetics; TP53; transcriptome; Tumor Suppressor Protein p53 - genetics; upper urinary tract urothelial carcinoma; Ureteral Neoplasms - diagnosis; Ureteral Neoplasms - genetics; Ureteral Neoplasms - mortality; urothelial carcinoma; upper urinary tract urothelial carcinoma; urothelial carcinoma; RAS; transcriptome; molecular diagnostic; FGFR3; TP53; molecular classification; hypermutation; integrated molecular study
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2021.05.008

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC. [Display omitted] •A few genes differ on alteration frequencies in UTUC and UBC•UTUC comprises five molecular subtypes: hypermutated, TP53/MDM2, RAS, FGFR3, and TN•UTUC subtypes correlate with gene expression, histology, and clinical outcomes•Sequencing urinary sediment is a non-invasive diagnostic tool for UTUC Based on an integrated genomic analysis of 199 upper urinary tract urothelial carcinomas (UTUCs), Fujii et al. identify five genetic subtypes with discrete profile of gene mutation, expression, histology, and clinical outcome and also demonstrate a high diagnostic value of sequencing urinary sediment-derived DNA for non-invasive detection of UTUCs.