MP58-09 COMPREHENSIVE ANALYSIS OF UPPER URINARY TRACT UROTHELIAL CARCINOMA

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2018MP58-09 COMPREHENSIVE ANALYSIS OF UPPER URINARY TRACT UROTHELIAL CARCINOMA Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Yusuke Shiozawa, Kenichi Yoshida, Yuichi Shiraishi, Tohru Nakagawa, Hiroaki Nishimatsu, Masashi Sanada, Hideki Makishima, Satoru Miyano, Seishi Ogawa, and Haruki Kume 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 , Hiroaki NishimatsuHiroaki Nishimatsu 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 Haruki KumeHaruki Kume More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1841AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Upper urinary tract urothelial carcinoma (UTUC) is a relatively rare disease which accounts for 5-10% of all urothelial malignancies, and its molecular biology is poorly understood. We comprehensively investigated the genetic alterations of this disease. METHODS Surgical specimens of UTUC and matched normal samples were obtained from 102 patients with various stages who underwent nephroureterectomy, and were subjected to whole exome/RNA sequencing and methylation array. RESULTS UTUC displayed a large number of mutations with 5.3 mutations per megabase (Mb). 7 cases showed hypermutation (>20/Mb), 6 of which harbored biallelic mismatch repair (MMR) gene alterations, supporting UTUC is a Lynch syndrome-associated cancer. Genetic alterations were most frequently observed in TERT promoter (51% of cases), followed by KMT2D (48%), FGFR3 (46%, including fusion genes), CDKN2A (homozygous deletion) (42%), TP53 (31%), and RAS family genes (HRAS/KRAS/NRAS, 21%). More than 95% cases harbored either TP53, MDM2, FGFR3, or RAS alterations in almost mutually exclusive manner. Hierarchical clustering of frequently altered genes in 95 non-hypermutated cases identified 3 distinct subgroups. Group 1 is characterized by frequent TP53/MDM2 alterations with complex copy number alterations (CNAs), high stage/grade, and poor prognosis. Group2 is enriched in FGFR3 and CDKN2A alterations, showing simple CNAs, low stage/grade, and favorable prognosis. All cases in Group3 harbored RAS-family gene alterations. Gene expression analysis with unsupervised clustering identified 3 clusters. Cluster 1 was enriched for TP53 defective cases, showing high expression of late cell-cycle genes and basal markers. On the other hand, cluster 2 and 3 showed high expression of early cell cycle genes and luminal markers. Cases in cluster 2 were mainly FGFR3-mutanted cases (75%) while almost all of the RAS-mutated cases were classified in cluster 3 (92%). Notably, cluster 1, which showed poor prognosis, had significantly high expression of the immune blockade target CD274 and PDCD1LG2.Hierarchical analysis of methylation data revealed that approximately 60% of examined samples showed extensive hypermethylation (CIMP+). However, there was no significant correlation with the mutation subtypes. CONCLUSIONS UTUC showed distinct genetic landscape in terms of mutations, which was also associated with prognosis, clinical features, and expression pattern. Our findings of molecular characteristics of UTUC will contribute to the development of new potential diagnostics and therapeutics. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e776 Advertisement Copyright & Permissions© 2018MetricsAuthor 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 Hiroaki Nishimatsu 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 Haruki Kume More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...