Pseudogene associated recurrent gene fusion in prostate cancer

Abstract

27 Analysis of next generation transcriptome sequencing data of prostate cancer 28 identified a novel gene fusion formed by the fusion of a protein coding gene (KLK4) with a 29 non-coding pseudogene (KLKP1) and expression of its cognate protein. Screening of 659 30 prostate cancer TMA showed about 32% of positive cases predominantly expressed in 31 higher Gleason grade tumors. Concomitant expression with ERG but not with SPINK1 and 32 other ETS fusion positive tumors. Fusion gene expression potentially regulated by AR and 33 ERG. Antibody specific to the KLK4-KLKP1 fusion protein was validated by 34 immunohistochemistry and western blot methods. Oncogenic properties were validated by 35 in vitro and in vivo functional studies. Clinical data analysis shows significant association 36 with prostate cancer in young men and overall survival analysis indicate favorable prognosis. 37 Non-invasive detection in urine samples has been confirmed. Taken together, we present a 38 novel biomarker for routine screening of high Gleason grade prostate cancer at diagnosis. 39 40 SIGNIFICANCE 41We discovered and validated a novel prostate cancer (PCa) specific fusion gene involving 42 a protein coding (KLK4) and a pseudogene (KLKP1) and its cognate protein. The unique feature 43 of this fusion gene is the conversion of the noncoding pseudogene into a protein coding gene and 44 its unique expression only in about 30% of high Gleason grade PCa. Expression of this gene is 45 found to be concomitant in ERG fusion positive prostate cancer but mutually exclusive with 46 SPINK1, ETV1, ETV4 and ETV5 positive tumors. Like other ETS family gene fusions, KLK4-47

Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization

“…(3) Additionally, another 5-10% of patients are reported to have SPINK1 overexpression (4), whereas 1-2% display RAF kinase gene fusions. ( 5) Recently, we reported the identification of a pseudogene associated recurrent gene fusion KLK4-KLKP1 present predominantly in ERG fusion positive tumors (6). Emerging evidence suggests that distinct molecular aberrations have distinct functional roles in prostate cancer and potentially implicated in varying clinical outcomes.…”

Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization

“…(3) Additionally, another 5-10% of patients are reported to have SPINK1 overexpression (4), whereas 1-2% display RAF kinase gene fusions. (5) Recently, we reported the identification of a pseudogene associated recurrent gene fusion KLK4-KLKP1 present predominantly in ERG fusion positive tumors (6). Emerging evidence suggests that distinct molecular aberrations have distinct functional roles in prostate cancer and potentially implicated in varying clinical outcomes.…”