DNA repair deregulation in discrete prostate cancer lesions identified on multi-parametric MRI and targeted by MRI/ultrasound fusion-guided biopsy

Abstract

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.

Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis

“…DNA damage repair pathway defects play an important role in prostate cancer carcinogenesis and progression, and mutations are present in around 19% of prostate tumours of Gleason grade ≥ 8 [31] ; these also appear to play a role in tumour conspicuity on mpMRI. Dulaney et al [27] noted significantly higher deregulation of DNA repair–related genes in mpMRI-visible targeted tumours with higher dynamic contrast enhancement values, as also noted in other studies [26] . Another case study found lower ADC values in tumour regions with a greater number of copy-number alterations and higher mutational burden [32] .…”

“…Li and colleagues [26] reported enriched processes of mitotic cell cycle, protein folding, cell cycle, mitotic cell cycle process, and cell division in mpMRI-visible cancers. Furthermore, Dulaney and colleagues [27] reported that tumours with a PI-RADS score of 5 had significantly more deregulation of pathways involved in apoptosis and cell cycle (in particular, TGFβ, STAT, and RAS pathways) compared with mpMRI-invisible tumours; however, this was unadjusted for multiple testing and this study scored relatively low using the modified Newcastle-Ottawa scale (3/8), indicating a potential a risk of bias. Finally, Beksac et al [17] reported that pathways associated with CCP (PI3K-AKT-mTOR and E2F) and castration resistance (WNT-b) were found to be more active in mpMRI-visible cancer (PI-RADSv2 score of 5) than in mpMRI-invisible cancer.…”

Conspicuity of prostate cancer on multiparametric magnetic resonance imaging: A cross‐disciplinary translational hypothesis

“…42 We previously identified DNA damage as a key element of the genetic determinants of tumor visibility on mpMRI, from previous studies that demonstrated that tumors with higher DCE values (ie, tumors that are visible on the contrast mpMRI sequence) had significantly higher deregulation of DNA repair-related genes, compared to tumors with lower DCE values. 43 Li and colleagues also found that DNA damage repair pathway abnormalities were enriched in mpMRI-visible tumors. 33 Together, these studies provide support for our hypothesis, given that pronounced DNA repair abnormalities found in mpMRI-visible disease are likely to contribute to an adverse clinical prognosis.…”

“…Tumor hypoxia is known to downregulate DNA double strand break repair gene expression in prostate cancer cells such as: Rad51, Rad52, Rad54, BRCA1, BRCA2 , leading to an increase in DNA damage 42 . We previously identified DNA damage as a key element of the genetic determinants of tumor visibility on mpMRI, from previous studies that demonstrated that tumors with higher DCE values (ie, tumors that are visible on the contrast mpMRI sequence) had significantly higher deregulation of DNA repair‐related genes, compared to tumors with lower DCE values 43 . Li and colleagues also found that DNA damage repair pathway abnormalities were enriched in mpMRI‐visible tumors 33 .…”

Entering an era of radiogenomics in prostate cancer risk stratification

“…However, we believe the “glass is half full”. While these tests may not overcome the issue of heterogeneity, they do address it and provide a level of risk stratification beyond pathology alone that can be helpful in select cases ( 46 ).…”