TY - JOUR
T1 - Pseudogene Associated Recurrent Gene Fusion in Prostate Cancer
AU - Chakravarthi, Balabhadrapatruni VSK
AU - Dedigama-Arachchige, Pavithra
AU - Carskadon, Shannon
AU - Sundaram, Shanker Kalyana
AU - Li, Jia
AU - Wu, Kuan Han Hank
AU - Chandrashekar, Darshan Shimoga
AU - Peabody, James O.
AU - Stricker, Hans
AU - Hwang, Clara
AU - Chitale, Dhananjay A.
AU - Williamson, Sean R.
AU - Gupta, Nilesh S.
AU - Navone, Nora M.
AU - Rogers, Craig
AU - Menon, Mani
AU - Varambally, Sooryanarayana
AU - Palanisamy, Nallasivam
N1 - Funding Information:
Funding: National Cancer Institute, grant number: R21CA176330; Department of Defense -CDMRP W81XWH-16-1-0544 and Dykstra Foundation to N. P. We would like to thank Mireya Diaz-Insua for her help with identifying the prostate patient cohort; Natalia Draga and Jingli Yang for constructing the prostate tissue microarray; and Arul Chinnaiyan at the Michigan Center for Translational Pathology, University of Michigan, for his support during the early phase of the project. We also thank the University of Michigan Sequencing Core and Vector Core facilities for their assistance in sequencing of the clones and construction of the adenoviral and lentiviral constructs used in the study. Conception and design: N. P. Development and methodology: S. V. N. P. Acquisition of data: B. V. S. K. C. P. D. A. S. C. N.P. Analysis and interpretation of data: S. K. J. L. K. H. H. W. D. S. C. N. P. S. V. P. D. A. N. G. S. W. D. C. N. P. Writing, review, and/or revision of the manuscript: P. D. A. N. P. Administrative, technical, or material support: N. N. J. P. H. S. C. R. M. M. Study supervision: S. V. N. P.
Publisher Copyright:
© 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, and ETV5. Development of an antibody specific to KLK4-KLKP1 fusion protein confirmed the expression of the full-length KLK4-KLKP1 protein in prostate tissues. The in vitro and in vivo functional assays to study the oncogenic properties of KLK4-KLKP1 confirmed its role in cell proliferation, cell invasion, intravasation, and tumor formation. Presence of strong ERG and AR binding sites located at the fusion junction in KLK4-KLKP1 suggests that the fusion gene is regulated by ERG and AR. Correlative analysis of clinical data showed an association of KLK4-KLKP1 with lower preoperative PSA values and in young men (<50 years) with prostate cancer. Screening of patient urine samples showed that KLK4-KLKP1 can be detected noninvasively in urine. Taken together, we present KLK4-KLKP1 as a class of pseudogene associated fusion transcript in cancer with potential applications as a biomarker for routine screening of prostate cancer.
AB - We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, and ETV5. Development of an antibody specific to KLK4-KLKP1 fusion protein confirmed the expression of the full-length KLK4-KLKP1 protein in prostate tissues. The in vitro and in vivo functional assays to study the oncogenic properties of KLK4-KLKP1 confirmed its role in cell proliferation, cell invasion, intravasation, and tumor formation. Presence of strong ERG and AR binding sites located at the fusion junction in KLK4-KLKP1 suggests that the fusion gene is regulated by ERG and AR. Correlative analysis of clinical data showed an association of KLK4-KLKP1 with lower preoperative PSA values and in young men (<50 years) with prostate cancer. Screening of patient urine samples showed that KLK4-KLKP1 can be detected noninvasively in urine. Taken together, we present KLK4-KLKP1 as a class of pseudogene associated fusion transcript in cancer with potential applications as a biomarker for routine screening of prostate cancer.
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U2 - 10.1016/j.neo.2019.07.010
DO - 10.1016/j.neo.2019.07.010
M3 - Article
C2 - 31446281
AN - SCOPUS:85070905024
SN - 1522-8002
VL - 21
SP - 989
EP - 1002
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 10
ER -