Characterization of KRAS rearrangements in metastatic prostate cancer.


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.

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.

  • Asangani IA
  • Ateeq B
  • Cantley LC
  • Cao Q
  • Cao X
  • Chinnaiyan AM
  • Dhanasekaran SM
  • Fries DF
  • Gopalan A
  • Han B
  • Jing X
  • Kahoud ER
  • Li Y
  • Omenn GS
  • Palanisamy N
  • Pflueger D
  • Prensner JR
  • Reuter VE
  • Robinson D
  • Rubin MA
  • Sasaki AT
  • Shankar S
  • Varambally S
  • Wang R
  • Wang XS
  • Yocum AK
PubMed ID
Appears In
Cancer Discov, 2011, 1 (1)