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

Wang, C; Block, MS; Cunningham, JM; Sherman, ME; McCauley, BM; Armasu, SM; Vierkant, RA; Traficante, N; Australian Ovarian Cancer Study Group; Talhouk, A; Ramus, SJ; Pejovic, N; Kobel, M; Jorgensen, BD; Garsed, DW; Fereday, S; Doherty, JA; Ariyaratne, D; Anglesio, MS; Widschwendter, M; Pejovic, T; Gonzalez Bosquet, J; Bowtell, DD; Winham, SJ; Goode, EL

Author(s): Wang, C; Block, MS; Cunningham, JM; Sherman, ME; McCauley, BM; Armasu, SM; Vierkant, RA; Traficante, N; Australian Ovarian Cancer Study Group; Talhouk, A; Ramus, SJ; Pejovic, N; Kobel, M; Jorgensen, BD; Garsed, DW; Fereday, S; Doherty, JA; Ariyaratne, D; Anglesio, MS; Widschwendter, M; Pejovic, T; Gonzalez Bosquet, J; Bowtell, DD; Winham, SJ; Goode, EL;
Details: Publication Year 2023-04-03,Volume 32,Issue #4,Page 542-549
Journal Title: Cancer Epidemiology, Biomarkers & Prevention
Publication Type: Research article
Abstract: 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 that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), 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, hazard ratio (HR), 1.65; 95% confidence interval (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.
Publisher: American Association for Cancer Research
Keywords: Female; Humans; *Ovarian Neoplasms/pathology; Prognosis; *Cystadenocarcinoma, Serous/genetics/pathology; Proportional Hazards Models; DNA Methylation; Biomarkers, Tumor/genetics/metabolism; Tumor Microenvironment/genetics
Department(s): Laboratory Research
PubMed ID: 36790339
Publisher's Version: https://doi.org/10.1158/1055-9965.EPI-22-0941
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-05 06:33:35

Last Modified: 2024-07-30 02:09:30