DNA repair deregulation in discrete prostate cancer lesions identified on multi-parametric MRI and targeted by MRI/ultrasound fusion-guided biopsy
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Caleb R. Dulaney1, Soroush Rais-Bahrami2,3, Debra Della Manna1, Jennifer B. Gordetsky4, Jeffrey W. Nix2 and Eddy S. Yang1,5,6
1Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA
2Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA
3Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA
4Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
5Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
6Department of Pharmacology and Toxicology University of Alabama at Birmingham, Birmingham, AL, USA
Eddy S. Yang, email: firstname.lastname@example.org
Keywords: prostatic neoplasms, DNA repair, magnetic resonance imaging, image-guided biopsy
Received: January 20, 2017 Accepted: June 02, 2017 Published: July 10, 2017
Prostate cancer is histologically and molecularly heterogeneous. Clinically significant disease is often driven by dominant intra-prostatic lesions (IPLs). Prostate cancers cluster into molecular phenotypes with substantial genetic heterogeneity making pathway-based molecular analysis appealing. MRI/ultrasound fusion biopsy provides a unique opportunity to characterize tumor biology of discrete lesions at diagnosis. This study determined the feasibility of pathway-based gene expression analysis of prostate biopsies and characterized cancer pathway deregulation.
Thirteen patients had prostate cancer diagnosed by MRI/ultrasound fusion biopsy and either Gleason 6 or Gleason ≥8. Gene expression profiling was performed on 14 biopsies using >700 genes representing 13 cancer pathways. Pathway-based analysis compared gene expression among samples based on clinical, pathological, and radiographic characteristics. Pathway-based gene expression analysis was successful in 12 of 14 (86%) samples. Samples clustered based upon deregulation of DNA Repair and Notch, Chromatin Modification and Cell Cycle, or all other pathways, respectively. DNA Repair demonstrated the greatest differential deregulation. Lesions with Gleason ≥8, PSA ≥10, or intense dynamic contrast enhancement (DCE) had significantly higher DNA Repair deregulation than those with Gleason 6, PSA <10, or low to moderate DCE. Alterations in DNA Repair gene expression were diverse with upregulation of markers of DNA damage and down-regulation of DNA Repair proteins. This study demonstrates the feasibility of pathway-level gene expression analysis of discrete intra-prostatic lesions sampled by MRI/ultrasound fusion biopsy. IPLs cluster into distinct molecular phenotypes, the most significantly altered being DNA Repair.
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