Academic Journal
Comprehensive methylome sequencing reveals prognostic epigenetic biomarkers for prostate cancer mortality
| العنوان: | Comprehensive methylome sequencing reveals prognostic epigenetic biomarkers for prostate cancer mortality |
|---|---|
| المؤلفون: | Pidsley, Ruth, Lam, Dilys, Qu, Wenjia, Peters, Timothy J., Luu, Phuc‐Loi, Korbie, Darren, Stirzaker, Clare, Daly, Roger J., Stricker, Phillip, Kench, James G., Horvath, Lisa G., Clark, Susan J. |
| المصدر: | Clin Transl Med |
| بيانات النشر: | John Wiley and Sons Inc. Wiley |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Research Articles, demo, envir |
| الوصف: | BACKGROUND: Prostate cancer is a clinically heterogeneous disease with a subset of patients rapidly progressing to lethal‐metastatic prostate cancer. Current clinicopathological measures are imperfect predictors of disease progression. Epigenetic changes are amongst the earliest molecular changes in tumourigenesis. To find new prognostic biomarkers to enable earlier intervention and improved outcomes, we performed methylome sequencing of DNA from patients with localised prostate cancer and long‐term clinical follow‐up. METHODS: We used whole‐genome bisulphite sequencing (WGBS) to comprehensively map and compare DNA methylation of radical prostatectomy tissue between patients with lethal disease (n = 7) and non‐lethal (n = 8) disease (median follow‐up 19.5 years). Validation of differentially methylated regions (DMRs) was performed in an independent cohort (n = 185, median follow‐up 15 years) using targeted multiplex bisulphite sequencing of candidate regions. Survival was assessed via univariable and multivariable analyses including clinicopathological measures (log‐rank and Cox regression models). RESULTS: WGBS data analysis identified cancer‐specific methylation patterns including CpG island hypermethylation, and hypomethylation of repetitive elements, with increasing disease risk. We identified 1420 DMRs associated with prostate cancer‐specific mortality (PCSM), which showed enrichment for gene sets downregulated in prostate cancer and de novo methylated in cancer. Through comparison with public prostate cancer datasets, we refined the DMRs to develop an 18‐gene prognostic panel. Applying this panel to an independent cohort, we found significant associations between PCSM and hypermethylation at EPHB3, PARP6, TBX1, MARCH6 and a regulatory element within CACNA2D4. Strikingly in a multivariable model, inclusion of CACNA2D4 methylation was a better predictor of PCSM versus grade alone (Harrell's C‐index: 0.779 vs. 0.684). CONCLUSIONS: Our study provides detailed methylome maps of non‐lethal and lethal prostate . |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523674/ |
| الاتاحة: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9523674/ |
| Rights: | undefined |
| رقم الانضمام: | edsbas.2D48CFCE |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |