TY - JOUR
T1 - Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma
AU - Australian Ovarian Cancer Study Group
AU - Wang, Chen
AU - Block, Matthew S.
AU - Cunningham, Julie M.
AU - Sherman, Mark E.
AU - McCauley, Bryan M.
AU - Armasu, Sebastian M.
AU - Vierkant, Robert A.
AU - Traficante, Nadia
AU - Talhouk, Aline
AU - Ramus, Susan J.
AU - Pejovic, Nadja
AU - Köbel, Martin
AU - Jorgensen, Brooke D.
AU - Garsed, Dale W.
AU - Fereday, Sian
AU - Doherty, Jennifer A.
AU - Ariyaratne, Dinuka
AU - Anglesio, Michael S.
AU - Widschwendter, Martin
AU - Pejovic, Tanja
AU - Bosquet, Jesus Gonzalez
AU - Bowtell, David D.
AU - Winham, Stacey J.
AU - Goode, Ellen L.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/4/10
Y1 - 2023/4/10
N2 - Background: Better understanding of prognostic factors in tuboovarian 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 CD8þ 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 ¼ 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P ¼ 0.015; N ¼ 325 published set HR, 2.87; 95% CI, 2.17–3.81; P ¼ 2.2 * 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N ¼ 599; HR, 2.22; 95% CI, 1.66–2.95; P ¼ 4.1 * 10-8). Methylation signature was inversely related to CD8þ TIL levels (P ¼ 2.4 * 10-7) and TAP1 expression (P ¼ 0.0011) and was associated with gene expression molecular subtype (P ¼ 5.9 * 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.
AB - Background: Better understanding of prognostic factors in tuboovarian 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 CD8þ 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 ¼ 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10–2.46; P ¼ 0.015; N ¼ 325 published set HR, 2.87; 95% CI, 2.17–3.81; P ¼ 2.2 * 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N ¼ 599; HR, 2.22; 95% CI, 1.66–2.95; P ¼ 4.1 * 10-8). Methylation signature was inversely related to CD8þ TIL levels (P ¼ 2.4 * 10-7) and TAP1 expression (P ¼ 0.0011) and was associated with gene expression molecular subtype (P ¼ 5.9 * 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.
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U2 - 10.1158/1055-9965.EPI-22-0941
DO - 10.1158/1055-9965.EPI-22-0941
M3 - Article
C2 - 36790339
AN - SCOPUS:85151575083
SN - 1055-9965
VL - 32
SP - 542
EP - 549
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 4
ER -