Neoplasia. 2019 Aug 22;21(10):989-1002. doi: 10.1016/j.neo.2019.07.010. [Epub ahead of print]
Pseudogene Associated Recurrent Gene Fusion in Prostate Cancer.
Chakravarthi BV1, Dedigama-Arachchige P2, Carskadon S2, Sundaram SK3, Li J4, Wu KH4, Chandrashekar DS1, Peabody JO2, Stricker H2, Hwang C5, Chitale DA6, Williamson SR6, Gupta NS6, Navone NM7, Rogers C2, Menon M2, Varambally S8, Palanisamy N9.
Author information
- 1
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL.
- 2
- Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI.
- 3
- Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI.
- 4
- Department of Public Health Sciences, Henry Ford Health System, Detroit, MI.
- 5
- Department of Hematology and Oncology, Henry Ford Health System, Detroit, MI.
- 6
- Department of Pathology, Henry Ford Health System, Detroit, MI.
- 7
- Department of Genitourinary Medical Oncology-The University of Texas, M D, Anderson Cancer Center, TX.
- 8
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL.
- 9
- Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI. Electronic address: npalani1@hfhs.org.
Abstract
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 below 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.
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
- PMID:
- 31446281
- DOI:
- 10.1016/j.neo.2019.07.010
