TY - JOUR
T1 - Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer
AU - Wang, Chen
AU - Cicek, Mine S.
AU - Charbonneau, Bridget
AU - Kalli, Kimberly R.
AU - Armasu, Sebastian M.
AU - Larson, Melissa C.
AU - Konecny, Gottfried E.
AU - Winterhoff, Boris
AU - Fan, Jian Bing
AU - Bibikova, Marina
AU - Chien, Jeremy
AU - Shridhar, Viji
AU - Block, Matthew S.
AU - Hartmann, Lynn C.
AU - Visscher, Daniel W.
AU - Cunningham, Julie M.
AU - Knutson, Keith L.
AU - Fridley, Brooke L.
AU - Goode, Ellen L.
PY - 2014/6/1
Y1 - 2014/6/1
N2 - 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.
AB - 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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U2 - 10.1158/0008-5472.CAN-13-3198
DO - 10.1158/0008-5472.CAN-13-3198
M3 - Article
C2 - 24728075
AN - SCOPUS:84902133505
SN - 0008-5472
VL - 74
SP - 3084
EP - 3091
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -
