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

Oncotarget. 2016 Jan 19;7(3):2629-45. doi: 10.18632/oncotarget.6380.


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.

Keywords: MLL; bladder cancer; drug-resistance; tumor recurrence; whole-exome sequencing.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics*
  • Blotting, Western
  • Case-Control Studies
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Exome / genetics*
  • Female
  • GATA4 Transcription Factor / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation / genetics*
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Proto-Oncogene Protein c-ets-1 / genetics
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Biomarkers, Tumor
  • ETS1 protein, human
  • GATA4 Transcription Factor
  • GATA4 protein, human
  • KMT2A protein, human
  • Proto-Oncogene Protein c-ets-1
  • RNA, Messenger
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase