Novel variants in MLL confer to bladder cancer recurrence identified by whole-exome sequencing.

Song Wu,Luyun He,Zhao Yang,Meng Zhang,Chunxiao Liu,Liyan Zhang,Tengteng Bi,Qiaoling Li,Zhiming Cai,Xin Zhao,Xuehan Zhuang,Feida Li,Dan An,Yi Huang,Huan Liu,Chong Li,Peide Huang,Xiaojuan Sun,Yong Hou,Jingxiao Lu,Fangjian Zhou,Yongqiang Wang,Zusen Fan,Da Sun,Rui Ye,Guosheng Yang,Yitian Wang,Yuan Yu

doi:10.18632/oncotarget.6380

Abstract

Bladder cancer (BC) is distinguished by high rate of recurrence after surgery, but the underlying mechanisms remain poorly understood. Here we performed the whole-exome sequencing of 37 BC individuals including 20 primary and 17 recurrent samples in which the primary and recurrent samples were not from the same patient. We uncovered that MLL, EP400, PRDM2, ANK3 and CHD5 exclusively altered in recurrent BCs. Specifically, the recurrent BCs and bladder cancer cells with MLL mutation displayed increased histone H3 tri-methyl K4 (H3K4me3) modification in tissue and cell levels and showed enhanced expression of GATA4 and ETS1 downstream. What's more, MLL mutated bladder cancer cells obtained with CRISPR/Cas9 showed increased ability of drug-resistance to epirubicin (a chemotherapy drug for bladder cancer) than wild type cells. Additionally, the BC patients with high expression of GATA4 and ETS1 significantly displayed shorter lifespan than patients with low expression. Our study provided an overview of the genetic basis of recrudescent bladder cancer and discovered that genetic alterations of MLL were involved in BC relapse. The increased modification of H3K4me3 and expression of GATA4 and ETS1 would be the promising targets for the diagnosis and therapy of relapsed bladder cancer.

Highlights

Bladder cancer is the most common malignancy of urinary system after renal carcinoma worldwide
About 70% of the urothelial bladder carcinoma patients are diagnosed with superficial non-muscle-invasive tumors which are apt to recur with the rate of 31% to 78% within five years but not life-threatening [4], while about 30% of the patients succumb to muscle-invasive tumors with a high risk of death from distant metastases [5]
We introduced the specific mutations of MLL into bladder cancer cells with the method of CRISPR/ Cas9 and the mutated cell exhibited enhanced H3K4me3 modification and elevated expression of GATA4 and ETS1 downstream, which endowed bladder cancer cells with the capability of drug-resistance to chemotherapy drug epirubicin

Summary

Introduction

Bladder cancer is the most common malignancy of urinary system after renal carcinoma worldwide. An approximately 430,000 new cases and an estimated 150,300 deaths per year [1, 2]. Urothelial bladder www.impactjournals.com/oncotarget carcinoma (>90%) is the major type of bladder cancer and clinically divided into two major subtypes including non-muscle-invasive and muscle-invasive tumors [3]. About 70% of the urothelial bladder carcinoma patients are diagnosed with superficial non-muscle-invasive tumors which are apt to recur with the rate of 31% to 78% within five years but not life-threatening [4], while about 30% of the patients succumb to muscle-invasive tumors with a high risk of death from distant metastases [5]. Radical cystectomy, bricker operation combined with chemotherapy extend lifespan of BC patients, the problem of easy recurrence remains unsolved. It is very important to explicit the mechanisms of bladder cancer relapse

Methods

Results

Conclusion