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

Abstract

<div>AbstractBackground:<p>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.</p>Methods:<p>We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8<sup>+</sup> tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1.</p>Results:<p>Methylation signature was associated with shorter time to recurrence, independent of clinical factors (<i>N</i> = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; <i>P</i> = 0.015; <i>N</i> = 325 published set HR, 2.87; 95% CI, 2.17–3.81; <i>P</i> = 2.2 × 10<sup>−13</sup>) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (<i>N</i> = 599; HR, 2.22; 95% CI, 1.66–2.95; <i>P</i> = 4.1 × 10<sup>−8</sup>). Methylation signature was inversely related to CD8<sup>+</sup> TIL levels (<i>P</i> = 2.4 × 10<sup>−7</sup>) and TAP1 expression (<i>P</i> = 0.0011) and was associated with gene expression molecular subtype (<i>P</i> = 5.9 × 10<sup>−4</sup>) in covariate-adjusted analysis.</p>Conclusions:<p>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.</p>Impact:<p>This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.</p></div>