MP71-02 DISTINCT GENOMIC LANDSCAPE OF UPPER URINARY TRACT UROTHELIAL CARCINOMA

Abstract

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma I1 Apr 2017MP71-02 DISTINCT GENOMIC LANDSCAPE OF UPPER URINARY TRACT UROTHELIAL CARCINOMA Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Yusuke Shiozawa, Kenichi Yoshida, Yuichi Shiraishi, Tohru Nakagawa, Haruki Kume, Hiroaki Nishimatsu, Toshikazu Okaneya, Masashi Sanada, Hideki Makishima, Satoru Miyano, Seishi Ogawa, and Yukio Homma Yoichi FujiiYoichi Fujii More articles by this author , Yusuke SatoYusuke Sato More articles by this author , Hiromichi SuzukiHiromichi Suzuki More articles by this author , Tetsuichi YoshizatoTetsuichi Yoshizato More articles by this author , Yusuke ShiozawaYusuke Shiozawa More articles by this author , Kenichi YoshidaKenichi Yoshida More articles by this author , Yuichi ShiraishiYuichi Shiraishi More articles by this author , Tohru NakagawaTohru Nakagawa More articles by this author , Haruki KumeHaruki Kume More articles by this author , Hiroaki NishimatsuHiroaki Nishimatsu More articles by this author , Toshikazu OkaneyaToshikazu Okaneya More articles by this author , Masashi SanadaMasashi Sanada More articles by this author , Hideki MakishimaHideki Makishima More articles by this author , Satoru MiyanoSatoru Miyano More articles by this author , Seishi OgawaSeishi Ogawa More articles by this author , and Yukio HommaYukio Homma More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2258AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Upper urinary tract urothelial carcinoma (UTUC) is relatively rare and its molecular biology is poorly understood. To clarify distinct characteristics of UTUC, we comprehensively investigated the genetic alterations of this disease. METHODS Surgical specimens of UTUC and matched normal samples were obtained from 99 patients with various stages and subjected to whole exome and RNA sequencing. Apparently normal urothelial epithelia and preoperative urine sediments were also analysed in 5 cases. RESULTS Genetic alterations were most frequently observed in TERT promoter (51% of cases), followed by KMT2D (48%), FGFR3 (44%), CDKN2A (42%), TP53 (31%), and RAS pathway (HRAS/KRAS/NRAS, 21%). More than 95% of cases harbored either TP53/MDM2, FGFR3, or RAS pathway mutations in an almost mutually exclusive manner, based on which UTUCs are classified into 3 distinct subgroups with unique molecular and clinical features; FGFR3-mutated tumors showed a significantly better prognosis than those with TP53/MDM2 (p<0.001) and RAS pathway (p=0.010) lesions. We also found 4 hypermutated cases which harbored biallelic mutations in mismatch repair genes. To further clarify the unique feature of mutations in UTUC, the mutation patterns were compared with those of bladder urothelial carcinoma (BUC) using previously reported datasets. Although altered genes in UTUC were almost same as those of BUC, frequencies were substantially different in some genes such as KMT2D and RB1. In addition, mutation spectrum in UTUC were also different depending on the anatomical location; Most of the RAS pathway mutations were found in renal pelvis (p=0.0013) while KMT2D mutations were observed more frequently in ureter (p<0.0001). In the analysis of normal epithelia, some epithelia and primary tumors harbored shared mutations as well as their private ones, indicating that clonal precancerous area expands in normal epithelia. By contrast, in other epithelia, we also found driver gene mutations that were not shared by primary tumors, suggesting the presence of a mutagenic field effect on urothelial multiple occurence. We also detected mutations in urine sediments identical to primary tumors with similar allele frequencies, suggesting that sequencing urine may be useful for disease monitoring. CONCLUSIONS UTUC tumors are classified into 3 molecularly and clinically distinct subtypes based on the status of mutations in TP53/MDM2, FGFR3, and RAS pathway. Depending on their location, urothlial cancers have different genetic backgrounds, where a field effect and clonal expansion might contribute to multifocal occurrence of UTUC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e944-e945 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Yoichi Fujii More articles by this author Yusuke Sato More articles by this author Hiromichi Suzuki More articles by this author Tetsuichi Yoshizato More articles by this author Yusuke Shiozawa More articles by this author Kenichi Yoshida More articles by this author Yuichi Shiraishi More articles by this author Tohru Nakagawa More articles by this author Haruki Kume More articles by this author Hiroaki Nishimatsu More articles by this author Toshikazu Okaneya More articles by this author Masashi Sanada More articles by this author Hideki Makishima More articles by this author Satoru Miyano More articles by this author Seishi Ogawa More articles by this author Yukio Homma More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...