4.5 Article

Methylation Subtypes of Primary Prostate Cancer Predict Poor Prognosis

Journal

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
Volume 31, Issue 7, Pages 1473-1482

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1055-9965.EPI-22-0007

Keywords

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Funding

  1. NCI [R01 CA222833, T32 CA094880]
  2. NCI Training Grant [K05 CA175147]
  3. NIH [R01 CA056678, R01 CA092579, P50 CA097186, P30 CA015704]
  4. Fred Hutchinson/University of Washington Cancer Consortium [S10OD028685]
  5. Cancer Center Support Grants (CCSG)
  6. NIH/NCI [P30CA016042]
  7. NCI Early Detection Research Network [1U01CA214194-01]
  8. Prostate Cancer Canada
  9. Canadian Cancer Society

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This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy. The subtype was found to be associated with an increased hazard of recurrence and mortality in three separate patient populations.
Background: Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. Methods: We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. Results: Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. Conclusions: A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. Impact: This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.

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