Characterization of KRAS rearrangements in metastatic prostate cancer.
Abstact
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.
Authors
- 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