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Updated: Oct 16, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Histologically benign PI-RADS 4 and 5 lesions contain cancer-associated epigenetic alterations
Ceren Şeref1, Ömer Acar2, Mert Kılıç3
1Department of Health Sciences, Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.
Background:
The detection rate of clinically significant prostate cancer has improved with the use of multiparametric magnetic resonance imaging (mpMRI). Yet, even with MRI-guided biopsy 15%-35% of high-risk lesions (Prostate Imaging-Reporting and Data System [PI-RADS] 4 and 5) are histologically benign. It is unclear if these false positives are due to diagnostic/sampling errors or pathophysiological alterations. To better understand this, we tested histologically benign PI-RAD 4 and 5 lesions for common malignant epigenetic alterations.
Materials And Methods:
MRI-guided in-bore biopsy samples were collected from 45 patients with PI-RADS 4 (n = 31) or 5 (n = 14) lesions. Patients had a median clinical follow-up of 3.8 years. High-risk mpMRI patients were grouped based on their histology into biopsy positive for tumor (BPT; n = 28) or biopsy negative for tumor (BNT; n = 17). From these biopsy samples, DNA methylation of well-known tumor suppressor genes (APC, GSTP1, and RARβ2) was quantified.
Results:
Similar to previous work we observed high rates of promoter methylation at GSTP1 (92.7%), RARβ2 (57.3%), and APC (37.8%) in malignant BPT samples but no methylation in benign TURP chips. Interestingly, similar to the malignant samples the BNT biopsies also had increased methylation at the promoter of GSTP1 (78.8%) and RARβ2 (34.6%). However, despite these epigenetic alterations none of these BNT patients developed prostate cancer, and those who underwent repeat mpMRI (n = 8) demonstrated either radiological regression or stability.
Conclusions:
Histologically benign PI-RADS 4 and 5 lesions harbor prostate cancer-associated epigenetic alterations.
Insights
Even with advanced MRI, some high-risk prostate lesions are benign. These benign lesions show epigenetic alterations similar to cancer, suggesting they are not false positives but a distinct biological entity.
Area of Science:
- Oncology
- Genetics
- Radiology
Background:
- Multiparametric magnetic resonance imaging (mpMRI) improves prostate cancer detection.
- However, 15-35% of high-risk lesions (PI-RADS 4-5) biopsied are benign, raising questions about diagnostic accuracy.
- The underlying cause of these false positives remains unclear, prompting investigation into epigenetic alterations.
Purpose of the Study:
- To investigate whether histologically benign PI-RADS 4 and 5 lesions exhibit common malignant epigenetic alterations.
- To differentiate between diagnostic errors and true pathophysiological changes in MRI-detected benign prostate lesions.
Main Methods:
- Collected MRI-guided biopsy samples from 45 patients with PI-RADS 4 or 5 lesions.
- Categorized patients into biopsy positive for tumor (BPT) or biopsy negative for tumor (BNT) groups.
- Quantified DNA methylation of tumor suppressor genes (APC, GSTP1, RARβ2) in biopsy samples.
Main Results:
- High promoter methylation rates for GSTP1, RARβ2, and APC were observed in malignant BPT samples.
- BNT biopsies showed significantly increased methylation at GSTP1 (78.8%) and RARβ2 (34.6%) promoters, similar to malignant samples.
- None of the BNT patients developed prostate cancer during a median 3.8-year follow-up, with some showing lesion regression or stability on repeat MRI.
Conclusions:
- Histologically benign PI-RADS 4 and 5 lesions possess prostate cancer-associated epigenetic alterations.
- These findings suggest that benign PI-RADS 4-5 lesions may represent a distinct biological entity rather than diagnostic or sampling errors.
- Further research into these epigenetic changes could refine diagnostic strategies for prostate cancer.
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