Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida
Cancer Res. 2014 Jun 1;74(11):3084-91. doi: 10.1158/0008-5472.CAN-13-3198. Epub 2014 Apr 11.
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.
为了揭示高级别浆液性（HGS）上皮性卵巢癌（EOC）临床转归的生物学机制，我们评估了肿瘤表观遗传变化与无复发生存时间（TTR）之间的关联。我们评估了 337 名梅奥诊所（明尼苏达州罗切斯特）患者肿瘤中约 450,000 个全基因组 CpG 的甲基化。使用发现（n=168）和验证（n=169）组的半监督聚类来确定具有临床意义的甲基化类别。聚类基于 60 个信息性 CpG 确定了两个甲基化类别，这些类别在验证集中的 TTR 不同[R 与 L 类，P=2.9×10(-3)，HR=0.52；95%置信区间（CI），0.34-0.80]。随访分析考虑了患者亚组的全基因组肿瘤 mRNA 表达（n=104）和 CD8 T 细胞浸润（n=89）。R 类中位于 6p21.3 的 CpG 低甲基化与免疫反应过程中基因的顺式上调相关（TAP1、PSMB8、PSMB9、HLA-DQB1、HLA-DQB2、HLA-DMA 和 HLA-DOA），增加了 CD8 T 细胞肿瘤浸润（P=7.6×10(-5)），并调节了免疫相关途径中的基因（P=1.6×10(-32)）。这是迄今为止对上皮性卵巢癌肿瘤甲基化与临床结局相关的最全面评估。综上所述，这些结果表明，受表观遗传调控的免疫反应是预测 HGS EOC 复发和可能治疗反应的指标。
