Journal
CANCER DISCOVERY
Volume 1, Issue 1, Pages 35-43Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8274.CD-10-0022
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Funding
- Early Detection Research Network [UO1 CA111275]
- Prostate SPORE [P50CA69568]
- National Center for Integrative Bioinformatics [U54 DA21519-01A1]
- NIH [R01CA132874]
- National Functional Genomics Center [W81XWH-09-2-0014, R01 CA125612-01, R01 CA132874]
- Prostate Cancer Foundation
- Doris Duke Charitable Foundation
- Burroughs Wellcome Foundation
- Kanae Foundation for Research Abroad
- Genentech Fellowship
- [P01 CA089021]
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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. Cancer Discovery; 1(1); 35-43. (C) 2011 AACR.
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