title: Characterization of KRAS rearrangements in metastatic prostate cancer.
abstract: Using an integrative genomics approach called amplification breakpoint ranking and assembly analysis, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line, originally derived from prostate cancer metastasis to the brain. Interestingly, analysis of tissues revealed that 2 of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion protein, a specific knockdown of which attenuates cell invasion and xenograft growth. Ectopic expression of the UBE2L3-KRAS fusion protein exhibits transforming activity in NIH 3T3 fibroblasts and RWPE prostate epithelial cells in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates MEK/ERK signaling, commonly engaged by oncogenic mutant KRAS, and instead signals via AKT and p38 mitogen-activated protein kinase (MAPK) pathways. This is the first report of a gene fusion involving the Ras family, suggesting that this aberration may drive metastatic progression in a rare subset of prostate cancers.
  
  
  CONCLUSIONS
  This is the first description of an oncogenic gene fusion of KRAS, one of the most studied proto-oncogenes. KRAS rearrangement may represent the driving mutation in a rare subset of metastatic prostate cancers, emphasizing the importance of RAS-RAF-MAPK signaling in this disease.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: Wang
authors.forename: Sunita
authors.initials: S
authors.lastname: Shankar
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.forename: Bushra
authors.initials: B
authors.lastname: Ateeq
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Jing
authors.forename: Daniel
authors.initials: D
authors.lastname: Robinson
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.forename: John R
authors.initials: JR
authors.lastname: Prensner
authors.forename: Anastasia K
authors.initials: AK
authors.lastname: Yocum
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Fries
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.forename: Irfan A
authors.initials: IA
authors.lastname: Asangani
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Gilbert S
authors.initials: GS
authors.lastname: Omenn
authors.forename: Dorothee
authors.initials: D
authors.lastname: Pflueger
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gopalan
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Emily Rose
authors.initials: ER
authors.lastname: Kahoud
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.forename: Sooryanarayana
authors.initials: S
authors.lastname: Varambally
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics; D050939:Gene Fusion; D015321:Gene Rearrangement; D057809:HEK293 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D044763:Ubiquitin-Conjugating Enzymes; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins