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

被引：0

作者：

Wang, Chen ^{[1
]}

Block, Matthew S. ^{[2
,3
]}

Cunningham, Julie M.

Sherman, Mark E. ^{[4
]}

McCauley, Bryan M. ^{[5
]}

Armasu, Sebastian M. ^{[5
]}

Vierkant, Robert A. ^{[1
]}

Traficante, Nadia ^{[7
]}

Talhouk, Aline ^{[9
,10
,11
]}

Doherty, Jennifer A. ^{[17
]}

Pejovic, Nadja ^{[14
]}

Kobel, Martin ^{[15
]}

Jorgensen, Brooke D. ^{[16
]}

Garsed, Dale W. ^{[6
]}

Fereday, Sian ^{[6
,7
]}

Ramus, Susan J. ^{[12
,13
]}

Ariyaratne, Dinuka ^{[6
]}

Anglesio, Michael S. ^{[9
,10
,18
]}

Widschwendter, Martin ^{[19
]}

Pejovic, Tanja ^{[20
,21
]}

Bosquet, Jesus Gonzalez ^{[22
]}

Bowtell, David D. ^{[6
]}

Winham, Stacey J. ^{[1
]}

Goode, Ellen L.

机构：

[1] Mayo Clin, Div Computat Biol, Dept Quantitat Hlth Sci, Rochester, MN USA

[2] Mayo Clin, Dept Oncol, Rochester, MN USA

[3] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[4] Mayo Clin, Dept Quantitat Hlth Sci, Jacksonville, FL USA

[5] Mayo Clin, Dept Quantitat Hlth Sci, Div Clin Trials & Biostat, Rochester, MN USA

[6] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[7] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia

[8] Univ Sydney, Westmead Hosp, Dept Gynaecol Oncol, Sydney, NSW, Australia

[9] Vancouver Gen Hosp, British Columbias Ovarian Canc Res OVCARE Program, BC Canc, Vancouver, BC, Canada

[10] Univ British Columbia, Vancouver, BC, Canada

[11] Univ British Columbia, Dept Obstet & Gynecol, Vancouver, BC, Canada

[12] Univ NSW Sydney, Fac Med, Sch Clin Med, Sydney, NSW, Australia

[13] Univ NSW Sydney, Lowy Canc Res Ctr, Adult Canc Program, Sydney, NSW, Australia

[14] St Louis Sch Med, St. Louis, MO USA

[15] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB, Canada

[16] Mayo Clin, Div Epidemiol, Dept Quantitat Hlth Sci, Rochester, MN USA

[17] Univ Utah, Huntsman Canc Inst, Dept Pop ulat Hlth Sci, Salt Lake City, UT USA

[18] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada

[19] Univ Innsbruck, European Translat Oncol Prevent & Screening EUTOP, Hall In Tirol, Austria

[20] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR USA

[21] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR USA

[22] Univ Iowa, Div Gynecol Oncol, Dept Obstet & Gynecol, Iowa City, IA USA

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2023年 / 32卷 / 03期

基金：

欧洲研究理事会; 英国医学研究理事会; 美国国家卫生研究院; 欧盟地平线“2020”; 澳大利亚国家健康与医学研究理事会;

关键词：

OVARIAN-CANCER; REGULARIZATION; SURVIVAL;

D O I：

10.1158/1055-9965.EPI-22-0941

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diag-nosis 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 evalu-ated 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 quantita- tive 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.

引用

页码：542 / 549

页数：8

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