학술논문
Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer
Document Type
article
Author
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
Source
Cancer Research. 74(11)
Subject
Language
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.