Characterization of KRAS rearrangements in metastatic prostate cancer

Xiao Song Wang, Sunita Shankar, Saravana M. Dhanasekaran, Bushra Ateeq, Atsuo T. Sasaki, Xiaojun Jing, Daniel Robinson, Qi Cao, John R. Prensner, Anastasia K. Yocum, Rui Wang, Daniel F. Fries, Bo Han, Irfan A. Asangani, Xuhong Cao, Yong Li, Gilbert S. Omenn, Dorothee Pflueger, Anuradha Gopalan, Victor E. ReuterEmily Rose Kahoud, Lewis C. Cantley, Mark A. Rubin, Nallasivam Palanisamy, Sooryanarayana Varambally, Arul M. Chinnaiyan

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Using an integrative genomics approach called amplification breakpoint ranking and assembly analysis, we nominated KRAS as a gene fusion with the ubiquitinconjugating 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.

Original languageEnglish (US)
Pages (from-to)35-43
Number of pages9
JournalCancer discovery
Volume1
Issue number1
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Oncology

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