Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent copy number variation in IPO11 and prognostic significance of importin-11 overexpression on poor survival.

Junjie Zhao,Zhensheng Zhang,Chong Ma,Chuanliang Xu,Weidong Xu,Yinghao Sun,Shuxiong Zeng,Minghui He

doi:10.18632/oncotarget.12315

Abstract

Non-muscle-invasive bladder cancer (NMIBC) often has a worse prognosis following its progression to muscle-invasive bladder cancer (MIBC), despite radical cystectomy with pelvic lymph node dissection combined with chemotherapy. Therefore, the discovery of novel biomarkers for predicting the progression of this disease and of therapeutic targets for preventing it is crucial. We performed whole-exome sequencing to analyze superficial tumor tissues (Tsup) and basal tumor tissues (Tbas) from 3 MIBC patients and identified previously unreported copy number variations in IPO11 that warrants further investigation as a molecular target. In addition, we identified a significant association between the absolute copy number and mRNA expression of IPO11 and found that high importin-11 expression was correlated with poor 3-year overall survival (OS), cancer-specific survival (CSS) and cancer-free survival (CFS) compared with low expression in the BCa patients. Importin-11 overexpression was also an independent risk factor for CSS and CFS in the BCa patients. Our study has revealed that IPO11 copy number amplification contributes to its overexpression and that these changes are unfavorable prognostic factors in NMIBC. Thus, IPO11 copy number amplification and importin-11 overexpression are promising biomarkers for predicting the progression and poor prognosis of patients with NMIBC.

Highlights

Bladder cancer (BCa) is the most prevalent urinary malignancy in China, with incidence and mortality rates of 80.5 and 32.9 per 100,000, respectively, in 2015 [1]
Non-muscle-invasive bladder cancer (NMIBC) often has a worse prognosis following its progression to muscle-invasive bladder cancer (MIBC), despite radical cystectomy with pelvic lymph node dissection combined with chemotherapy
A total of 905, 728, and 29 candidate somatic mutations were detected in the three comparisons, respectively, including 429 synonymous, 1066 missense, 112 nonsense, 30 splicing, 18 frameshift and 7 in-frame mutations, resulting in averages of 302, 243, and 10 somatic mutations, respectively, in exonic regions

Summary

Introduction

Bladder cancer (BCa) is the most prevalent urinary malignancy in China, with incidence and mortality rates of 80.5 and 32.9 per 100,000, respectively, in 2015 [1]. Approximately 70%80% present with non-muscle-invasive BCa (NMIBC). NMIBC is generally managed by transurethral tumor resection, a minimally invasive surgical treatment. NMIBC patients have a good prognosis if the disease has not progressed to muscle-invasive BCa (MIBC), and NMIBC eventually progresses to MIBC in approximately 30% of patients. Radical cystectomy with pelvic lymph node dissection is the standard treatment option for local. MIBC, but approximately 50% of patients still develop local recurrence within two years. The 3-year survival rate is less than 50% [2]. The molecular mechanisms underlying progression from NMIBC to MIBC are still poorly understood, and knowledge of the molecular biomarkers that predict the risk of clinical progression of NMIBC, as well as the targeted drugs that block this progression, is still lacking. Studies of the molecular mechanisms of BCa invasion and progression are necessary

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Conclusion