MP82-04 THE COPY NUMBER VARIATION SIGNATURES IN UPPER TRACT UROTHELIAL CARCINOMA DEFINE DISTINCT SUBTYPES WITH PROGNOSTIC RELEVANCE

Abstract

You have accessJournal of UrologyBladder Cancer: Upper Tract Transitional Cell Carcinoma II (MP82)1 Apr 2020MP82-04 THE COPY NUMBER VARIATION SIGNATURES IN UPPER TRACT UROTHELIAL CARCINOMA DEFINE DISTINCT SUBTYPES WITH PROGNOSTIC RELEVANCE Bao Guan, Huan Lu, Yuan Liang, Yanqing Gong, Shiming He, Qun He, Xuesong Li, Liqun Zhou*, and Weimin Ci Bao GuanBao Guan More articles by this author , Huan LuHuan Lu More articles by this author , Yuan LiangYuan Liang More articles by this author , Yanqing GongYanqing Gong More articles by this author , Shiming HeShiming He More articles by this author , Qun HeQun He More articles by this author , Xuesong LiXuesong Li More articles by this author , Liqun Zhou*Liqun Zhou* More articles by this author , and Weimin CiWeimin Ci More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000974.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To conduct an integrated analysis of copy-number signatures and identify its prognostic value in Upper tract urothelial carcinoma (UTUC). METHODS: We performed WGS in 90 UTUC primary tumor samples, and the preoperative urine cell-free DNA from 94 patients with urothelial carcinoma (26 UTUCs; 68 bladder cancers) were analyzed by shallow whole genome sequencing(WGS). Non-negative matrix factorization (NMF) was applied to resolve CNV signatures. Next we halved this cohort in terms of the median signature contribution, and outcomes of this classification were analyzed. An independent cohort from The Cancer Genome Atlas (TCGA) bladder cancer was also bisected around the median correlation between tumor CNV component and a CNV signature component, then the outcomes analysis were conducted. Association with survival was evaluated using Kaplan-Meier and multivariable Cox regression methods. All statistical tests were two-sided. RESULTS: This 90 UTUC cohort defined Six copy number signatures (Signature1-6). Cohort patients was classified to six groups (Sig1-6) according to copy number signature’s maximum contribution. Signature6 was correlated with SNV signature 3 and 11. Besides, mutational frequency of Sig6 in BER, NER and HR pathway is much higher than the other groups. Kaplan-Meier curves showed that Sig6 has a favorable outcome. Based on the ratio of CNV in genome and contribution of signature 6 in 90 UTUC patients, this cohort can be classified into three subgroups: 1) wGIIlow, which did not exhibit a dominant copy number variation whose wGII were less than 0.1, showed significantly higher number of age-related mutational signature 1 and was associated with positive lymph node, lower percentage of CD3+ lymphocyte and stromal TIMC; 2) sig6low, which possessed lower proportion of signature 6, is significantly relavant with Sessile tumor architecture; and 3) sig6high subgroup, which exhibited higher proportion of signature 6, showed higher ratio of microsatellite instability sites. Kaplan-Meier plots revealed that the sig6high subgroup exhibited favourable outcomes compared with the sig6low and wGII-low subgroup. In muscle-invasive UTUC patients, the sig6high subgroup also exhibited best outcomes, the wGIIlow subgroup shown the worst outcomes. In multivariate Cox regression proportional analyses adjusted for the effects of clinicopathologic variables, the contribution of sig6 were still an independent prognostic factor for CSS and MFS. we verified the predictive value of signature 6 in the TCGA bladder cohort, the sig6high group in the TCGA UCB cohort also show better overall survival and metastasis-free survival. CONCLUSIONS: A novel CNV signature maybe be a promising predictive biomarker for UTUC patients in future prospective clinical trials. Source of Funding: We thank Gengyan Xiong and Lei Zhang for scientific inputs about the manuscript as well as Han Hao, Qin Tang and Xiaoteng Yu for assistance with clinicopathological characterizations. This work was supported by CAS Strategic Priority Research Program (XDA16010102 to W.C.), the National Key R&D Program of China (2018YFC2000100 to W.C.), CAS (QYZDB-SSW-SMC039 to W.C.), the National Natural Science Foundation of China (7152146 to X.L., 81672541 to W.C. and 81672546 to L.Z.), K.C. Wong Education Foundation to W.C., the Clinical Features Research of Capital (Z151100004015173 to L.Z.), the Capital Health Research and Development of Special (2016-1-4077 to L.Z.). © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1246-e1247 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bao Guan More articles by this author Huan Lu More articles by this author Yuan Liang More articles by this author Yanqing Gong More articles by this author Shiming He More articles by this author Qun He More articles by this author Xuesong Li More articles by this author Liqun Zhou* More articles by this author Weimin Ci More articles by this author Expand All Advertisement PDF downloadLoading ...