Characterization of KRAS rearrangements in metastatic prostate cancer

Cancer Discov. 2011 Jun;1(1):35-43. doi: 10.1158/2159-8274.CD-10-0022. Epub 2011 Jun 1.

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.

Significance: 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.

Keywords: KRAS; bioinformatics; gene fusion; genomic amplification; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Gene Fusion
  • Gene Rearrangement*
  • HEK293 Cells
  • Humans
  • MAP Kinase Kinase Kinases / genetics
  • Male
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Prostatic Neoplasms / genetics*
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Ubiquitin-Conjugating Enzymes / genetics
  • p38 Mitogen-Activated Protein Kinases / genetics
  • ras Proteins / genetics*

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Ubiquitin-Conjugating Enzymes
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins