Tumor Hypomethylation at 6p21.3 Associates with Longer Time to Recurrence of High-Grade Serous Epithelial Ovarian Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-06, Vol.74 (11), p.3084-3091
• Main Authors: CHEN WANG, CICEK, Mine S, 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, CHARBONNEAU, Bridget, KALLI, Kimberly R, ARMASU, Sebastian M, LARSON, Melissa C, KONECNY, Gottfried E, WINTERHOFF, Boris, FAN, Jian-Bing, BIBIKOVA, Marina
• Format: Article
• Language: English
• Subjects: Adult; Antineoplastic agents; Biological and medical sciences; Carcinoma, Ovarian Epithelial; Chromosomes, Human, Pair 6; CpG Islands; DNA Methylation; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - immunology; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - immunology; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Pharmacology. Drug treatments; Tumors; Up-Regulation; Young Adult
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-3198

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.