Abstract 3405: Integrated analysis of urothelial carcinoma
Authors: Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Taketo Kawai, Tohru Nakagawa, Hiroaki Nishimatsu, Toshikazu Okaneya, Masashi Sanada, Hideki Makishima, Hiroyuki Aburatani, Satoru Miyano, Haruki Kume, Seishi Ogawa
Journal: Cancer Research (2019)

Abstract [Introduction] Accounting for 5-10% of all urothelial malignancies, upper urinary tract urothelial carcinoma (UTUC) is a relatively rare, whose molecular pathogenesis is poorly understood. We performed comprehensive genetic analysis in a large cohort of UTUC. [Materials and Methods] Surgical specimens of UTUC and matched normal samples were obtained from 209 patients with various stages who underwent nephroureterectomy, and were subjected to whole exome/RNA sequencing and methylation array. [Results] In total, we identified 33 significantly mutated genes (SMG) in UTUC, of which most frequently observed was the TERT promoter (53%), followed by KMT2D (46%), FGFR3 (42%), CDKN2A (42%), TP53 (35%), and RAS family genes (H-/K-/NRAS, 18%). More than 94% cases harbored either TP53, MDM2, FGFR3, or RASalterations in a largely mutually exclusive manner. Dirichlet process clustering based on the SMG identified 3 distinct subgroups. Group 1 cases were frequently affected by TP53, MDM2, and CCND1 alterations with complex copy number alterations (CNAs) and characterized by high stage/grade and poor prognosis. Group2 tumors were characterized by FGFR3 and CDKN2A alterations and associated with lower stage/grade and favorable prognosis, while all cases in Group3 harbored RAS-family gene alterations, showing intermediate prognosis. Gene expression analysis using unsupervised clustering identified 5 clusters. These subtypes showed strong correlation with the mutation status; cluster 1 was enriched for FGFR3 mutations, while clusters 3-5 were dominated by TP53 mutations. Most of the RAS-mutated cases were classified into cluster 2. Cluster 1,2, and 5 showed high expression of luminal markers, while clusters 3 and 4 showed high expression of basal markers. Cluster 5 also had strong expression of p53-like and EMT markers, showing a worse prognosis than other 2 luminal (+) subtypes. Cluster 3 was characterized by strong expression of SCC and immune markers, including CD274 and PDCD1LG2, with frequent squamous differentiation. Finally, clustering analysis combining UBC from TCGA revealed a close association between UTUC and UBC expression subtypes: cluster 1 was similar to the ‘luminal-papillary’ and ‘luminal’, cluster 5 to luminal-infiltrated’, and clusters 3 and 4 to ‘basal-squamous’. Interestingly, cluster 2 was totally different from any of the TCGA subgroups, which might represent an expression profile unique to UTUC. Hierarchical analysis of methylation data revealed that approximately 60% of examined samples showed CpG island methylator phenotype (CIMP). Although there was no correlation between mutation/expression subgroups and methylation profile, KMT2D mutations were significantly enriched in CIMP (-) cases (p=0.0063). [Conclusion] UTUC showed a distinct genetic landscape, associated with various clinical features. Our findings of molecular characteristics in UTUC will contribute to the development of novel diagnostics and therapeutics. Citation Format: Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Yuichi Shiraishi, Taketo Kawai, Tohru Nakagawa, Hiroaki Nishimatsu, Toshikazu Okaneya, Masashi Sanada, Hideki Makishima, Hiroyuki Aburatani, Satoru Miyano, Haruki Kume, Seishi Ogawa. Integrated analysis of urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3405.