1. Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer
- Author
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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, and Goode, Ellen L
- Subjects
Cancer ,Genetics ,Ovarian Cancer ,Biotechnology ,Human Genome ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Carcinoma ,Ovarian Epithelial ,Chromosomes ,Human ,Pair 6 ,CpG Islands ,DNA Methylation ,Female ,Humans ,Neoplasm Recurrence ,Local ,Neoplasms ,Glandular and Epithelial ,Ovarian Neoplasms ,Up-Regulation ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - 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.
- Published
- 2014