DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia

Stephanie S Kim; Seung Cho Lee; Bumjin Lim; Seung-Ho Shin; Mee Young Kim; Sol-Yi Kim; Hyeyeun Lim; Clémentine Charton; Dongho Shin; Hyong Woo Moon; Jinho Kim; Donghyun Park; Woong-Yang Park; Ji Youl Lee

doi:10.1016/j.prnil.2023.01.001

DNA methylation biomarkers distinguishing early-stage prostate cancer from benign prostatic hyperplasia

Prostate Int. 2023 Jun;11(2):113-121. doi: 10.1016/j.prnil.2023.01.001. Epub 2023 Jan 5.

Authors

Stephanie S Kim¹, Seung Cho Lee², Bumjin Lim³, Seung-Ho Shin², Mee Young Kim⁴, Sol-Yi Kim², Hyeyeun Lim², Clémentine Charton¹, Dongho Shin⁵, Hyong Woo Moon⁵, Jinho Kim¹, Donghyun Park², Woong-Yang Park^{2

6

7}, Ji Youl Lee^{4

5}

Affiliations

¹ Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, Korea.
² GENINUS Inc., Seoul, Korea.
³ Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
⁴ Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.
⁵ Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
⁶ Samsung Genome Institute, Samsung Medical Center, Seoul, Korea.
⁷ Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.

Abstract

Background: DNA methylation markers are considered robust diagnostic features in various cancer types, as epigenetic marks are commonly altered during cancer progression. Differentiation between benign prostatic hyperplasia (BPH) and early-stage prostate cancer (PCa) is clinically difficult, relying on the information of the patient's symptoms or levels of prostate-specific antigen.

Methods: A total of 42 PCa patients and 11 BPH patients were recruited. Genomic DNA was purified from tissues and used for the library preparation of the target-enriched methylome with enzymatic conversion and a Twist 85 Mbp EM-seq panel. Paired-end sequencing (150 bp) was performed using NovaSeq 6000 or NextSeq 550. After quality control, including adapter trimming and de-duplication of raw sequencing data, differential methylation patterns were analyzed between the BPH and PCa groups.

Results: We report DNA methylation patterns existing between BPH and PCa. The major finding is that broad hypermethylation occurred at genic loci in PCa tissues as compared to the BPH. Gene ontology analysis suggested that hypermethylation of genic loci involved in chromatin and transcriptional regulation is involved in cancer progression. We also compared PCa tissues with high Gleason scores to tissues with low Gleason scores. The high-Gleason PCa tissues showed hundreds of focal differentially methylated CpG sites corresponding to genes functioning in cancer cell proliferation or metastasis. This suggests that dissecting early-to-advanced-grade cancer stages requires an in-depth analysis of differential methylation at the single CpG site level.

Conclusions: Our study reports that enzymatic methylome sequencing data can be used to distinguish PCa from BPH and advanced PCa from early-stage PCa. The stage-specific methylation patterns in this study will be valuable resources for diagnostic purposes as well as further development of liquid biopsy approaches for the early detection of PCa.

Keywords: Benign prostatic hyperplasia; Biomarkers; Cancer diagnosis; DNA methylation; Enzymatic conversion; Gleason score; Prostate cancer; Target enrichment sequencing.