title: Novel variants in MLL confer to bladder cancer recurrence identified by whole-exome sequencing.
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.
authors.affiliation: The Affiliated Luohu Hospital of Shenzhen University, Shenzhen Luohu Hospital Group, Shenzhen, China.|Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.|CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Ye
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Dan
authors.initials: D
authors.lastname: An
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.|Anhui Medical University, Hefei, China.
authors.forename: Yitian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Feida
authors.initials: F
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Luyun
authors.initials: L
authors.lastname: He
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Da
authors.initials: D
authors.lastname: Sun
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Peide
authors.initials: P
authors.lastname: Huang
authors.affiliation: Anhui Medical University, Hefei, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Tengteng
authors.initials: T
authors.lastname: Bi
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Xuehan
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Jingxiao
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Fangjian
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Guangdong Second People's Hospital, Guangzhou, China.
authors.forename: Guosheng
authors.initials: G
authors.lastname: Yang
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Urological Surgery, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.|Anhui Medical University, Hefei, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D059472:Exome / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C494041:ETS1 protein, human; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; C497422:KMT2A protein, human; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase
keywords: MLL; bladder cancer; drug-resistance; tumor recurrence; whole-exome sequencing