Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma

Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature which we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TILs), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N=715 new set, HR 1.65, 95% CI 1.10-2.46, p=0.015; N=325 published set HR 2.87, 95% CI 2.17-3.81, p=2.2 x 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N=599, HR 2.22, 95% CI 1.66-2.95, p=4.1 x 10-8). Methylation signature was inversely related to CD8+ TIL levels (p=2.4 x 10-7) and TAP1 expression (p=0.0011) and was associated with gene expression molecular subtype (p=5.9 x 10-4) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. Bisulphite converted DNA from 36 samples were hybridised to the Illumina Infinium Methylation EPIC and 325 samples were hybridised to the Illumina InfiniumHumanMethylation 450 BeadChip. Data for 4 samples are not included in GEO submission (3 samples due to consent and 1 sample as a potential sample mix-up). All the other samples were previously made publicly available, as follows: TCGA methylation data are available via the cBioPortal for Cancer Genomics (https://www.cbioportal.org/; RRID:SCR_014555); other data are available on Gene Expression Omnibus (GEO; RRID:SCR_005012) under the following accession numbers: GSE65820, GSE211686, GSE72021, and GSE1333556.