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Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.

  • Author(s): Wang, Chen
  • Cicek, Mine S
  • Charbonneau, Bridget
  • Kalli, Kimberly R
  • Armasu, Sebastian M
  • Larson, Melissa C
  • Konecny, Gottfried E
  • Winterhoff, Boris
  • Fan, Jian-Bing
  • Bibikova, Marina
  • Chien, Jeremy
  • Shridhar, Viji
  • Block, Matthew S
  • Hartmann, Lynn C
  • Visscher, Daniel W
  • Cunningham, Julie M
  • Knutson, Keith L
  • Fridley, Brooke L
  • Goode, Ellen L
  • et al.
Abstract

To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P=2.9×10(-3), HR=0.52; 95% confidence interval (CI), 0.34-0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T-cell infiltration (n=89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P=7.6×10(-5)), and trans-regulation of genes in immune-related pathways (P=1.6×10(-32)). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.

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