Abstract 2456: Distinct genomic landscape of upper urinary tract urothelial carcinoma
Authors: Fujii Yoichi , Sato Yusuke , Suzuki Hiromichi , Yoshizato Tetsuichi , Shiozawa Yusuke , Yoshida Kenichi , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Nakagawa Tohru , Kume Haruki , Nishimatsu Hiroaki , Okaneya Toshikazu , Sanada Masashi , Makishima Hideki , Miyano Satoru , Homma Yukio , Ogawa Seishi 
Published: July 2017

Abstract
Backgrounds:
Upper urinary tract urothelial carcinoma (UTUC) is relatively rare, accounting for 5-10% of urothelial malignancies with frequent multifocal development. To clarify distinct characteristics of UTUC, we comprehensively investigated the genetic alterations of this disease.
Materials & methods:
Surgical specimens of UTUC and matched normal samples were obtained from 99 patients with various stages who underwent nephroureterectomy, and subjected to whole exome and RNA sequencing. We compared our results in UTUC with datasets previously reported in bladder urothelial carcinoma (BUC). Mutations in apparently normal urothelial epithelia in 5 cases were also interrogated.
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 postoperative overall survival than those with TP53/MDM2 (p&lt;0.001) and RAS pathway (p=0.010) lesions. KMT2D mutations were common in patients with TP53, MDM2, and FGFR3 alterations, but rare in those with RAS pathway alterations.
Mutation patterns were compared between different urothelial cancers with regard to their location. Despite common genes affected, their mutation frequencies were substantially different; KMT2D mutations were more frequent in UTUC, while RB1 alterations were more prevalent in BUC. In addition, KMT2D mutations were significantly more common in UTUCs in the ureter than those in renal pelvis (85% vs. 35%, p&lt;0.0001). UTUC showed 4 predominant mutation signatures; age-related, APOBEC, Transcriptional coupled repair (TCR), and mismatch repair (MMR) associated ones. Among these, TCR and MMR signatures were more specific to UTUC, although the latter is only detected in 4 hypermutated cases with biallelic MMR-gene deficiencies.
In the analysis of normal ureter tissues (N=25 from 5 patients), driver mutations were identified in 6 samples from 2 patients. In one case, tumor and normal samples shared 10-42 mutations, indicating that the cancer evolved within a background of clonal precancerous proliferation in apparently normal epithelia. By contrast, in the other case, none of the mutations were shared between tumors and normal epithelia, suggesting the presence of a field effect on urothelial carcinogenesis.
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 unique to urothelial epithelia might contribute to multifocal occurrence of UTUC.
Citation Format: Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Tetsuichi Yoshizato, Yusuke Shiozawa, Kenichi Yoshida, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Tohru Nakagawa, Haruki Kume, Hiroaki Nishimatsu, Toshikazu Okaneya, Masashi Sanada, Hideki Makishima, Satoru Miyano, Yukio Homma, Seishi Ogawa. Distinct genomic landscape of upper urinary tract urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2456. doi:10.1158/1538-7445.AM2017-2456