Copy Number Signatures and Clinical Outcomes in Upper Tract Urothelial Carcinoma

Bao Guan,Juan Li,Yue Shi,Liqun Zhou,Yuan Liang,Jin Liu,Zhengzheng Xu,Wenwen Kong,Shiming He,Chuanyu Tian,Yanqing Gong,Dong Fang,Qi Shen,Xuesong Li,Zhongyuan Zhang,Qun He,Muhammad Shakeel,Weimin Ci,Yezhen Tan,Huan Lü

doi:10.3389/fcell.2021.713499

Abstract

Tumor staging of upper tract urothelial carcinomas (UTUCs) is relatively difficult to assert accurately before surgery. Here, we used copy number (CN) signatures as a tool to explore their clinical significance of molecular stratification in UTUC. CN signatures were extracted by non-negative matrix factorization from the whole-genome sequencing (WGS) data of 90 Chinese UTUC primary tumor samples. A validation UTUC cohort (n = 56) and a cohort from urinary cell-free DNA (cfDNA) of urothelial cancer patients (n = 94) and matched primary tumors were also examined. Survival analyses were measured using the Kaplan–Meier, and Cox regression was used for multivariate analysis. Here, we identified six CN signatures (Sig1–6). Patients with a high contribution of Sig6 (Sig6high) were associated with higher microsatellite instability level and papillary architecture and had a favorable outcome. Patients with a low weighted genome integrity index were associated with positive lymph node and showed the worst outcome. Sig6high was identified to be an independently prognostic factor. The predictive significance of CN signature was identified by a validation UTUC cohort. CN signatures retained great concordance between primary tumor and urinary cfDNA. In conclusion, our results reveal that CN signature assessment for risk stratification is feasible and provides a basis for clinical studies that evaluate therapeutic interventions and prognosis.

Highlights

The European Association of Urology reported that 90–95% of urothelial carcinoma (UC) occurs as UC of the bladder (UCB), with upper tract UC (UTUC) accounting for 5–10% (Roupret et al, 2018)
17.8% patients had a history of smoking, and 30% patients had consumed aristolochic acid (AA)-containing drugs
Similar copy number (CN) profiles and CN signatures were derived from AA and no-AA cohort of patients (Lu et al, 2020; Supplementary Figure 7)

Summary

Introduction

The European Association of Urology reported that 90–95% of urothelial carcinoma (UC) occurs as UC of the bladder (UCB), with upper tract UC (UTUC) accounting for 5–10% (Roupret et al, 2018). Geographic differences in risk factors for UTUC, such as CN Signatures and UTUC aristolochic acid (AA)-containing herb drugs consumption, may account for the observation (Chen et al, 2012; Grollman, 2013; Hoang et al, 2013; Poon et al, 2013). Tumor stage of UTUC is usually difficult to be identified clinically by imageological examination (Roupret et al, 2018). It is useful to “risk stratify” UTUC between low- and high-risk tumors to identify those patients who are more suitable for kidney-sparing surgery or neoadjuvant treatment. Our previous study showed that AA mutational signature defines the low-risk subtype in UTUC (Lu et al, 2020). The genomic variation features may be promising predictive biomarkers for UTUC patients

Methods

Results

Conclusion