Novel variants in<i>MLL</i>confer to bladder cancer recurrence identified by whole-exome sequencing

Abstract

// Song Wu 1,4,* , Zhao Yang 2,3,* , Rui Ye 5,* , Dan An 5,* , Chong Li 2,* , Yitian Wang 4,6,* , Yongqiang Wang 7 , Yi Huang 4 , &nbsp;Huan Liu 5 , Feida Li 5 , Luyun He 2 , Da Sun 5 , Yuan Yu 5 , Qiaoling Li 5 , Peide Huang 5 , Meng Zhang 6 , Xin Zhao 5 , Tengteng Bi 5 , Xuehan Zhuang 5 , Liyan Zhang 5 , Jingxiao Lu 4 , Xiaojuan Sun 4 , Fangjian Zhou 7 , Chunxiao Liu 8 , Guosheng Yang 9 , Yong Hou 5 , Zusen Fan 2 and Zhiming Cai 4,6 1 The Affiliated Luohu Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, China 2 CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 3 CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China 4 Department of Urological Surgery, Shenzhen Second People&rsquo;s Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China 5 BGI-Shenzhen, Shenzhen, China 6 Anhui Medical University, Hefei, China 7 Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China 8 Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, China 9 Guangdong Second People&rsquo;s Hospital, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Zhiming Cai, email: // Zusen Fan, email: // Keywords : bladder cancer, tumor recurrence, MLL, drug-resistance, whole-exome sequencing Received : May 27, 2015 Accepted : October 14, 2015 Published : November 25, 2015 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&rsquo;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.