DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance.

IF 5.3 2区医学 Q1 ONCOLOGY JCO precision oncology Pub Date : 2024-11-01 Epub Date: 2024-11-07 DOI:10.1200/PO-24-00375

Kathleen Conway, Sharon N Edmiston, Amanda Vondras, Allison Reiner, David L Corcoran, Ronglai Shen, Eloise A Parrish, Honglin Hao, Lan Lin, Jessica M Kenney, Gbemisola Ilelaboye, Caroline E Kostrzewa, Pei Fen Kuan, Klaus J Busam, Cecilia Lezcano, Tim K Lee, Eva Hernando, Paul B Googe, David W Ollila, Stergios Moschos, Ivan Gorlov, Christopher I Amos, Marc S Ernstoff, Anne E Cust, James S Wilmott, Richard A Scolyer, Graham J Mann, Ismael A Vergara, Jennifer Ko, Judy R Rees, Shaofeng Yan, Eduardo Nagore, Marcus Bosenberg, Bonnie Gould Rothberg, Iman Osman, Jeffrey E Lee, Yvonne Saenger, Paul Bogner, Cheryl L Thompson, Meg Gerstenblith, Sheri L Holmen, Pauline Funchain, Elise Brunsgaard, Natalie D Depcik-Smith, Li Luo, Tawny Boyce, Irene Orlow, Colin B Begg, Marianne Berwick, Nancy E Thomas

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Abstract

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.

Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets.

Results: Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP (P = .01) and LM (P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM.

Conclusion: Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

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II期和III期原发性黑色素瘤的DNA甲基化分类及其临床和预后意义

目的：II期和III期皮肤原发性黑色素瘤患者的黑色素瘤相关死亡风险差异很大。我们探讨了甲基化分析区分原发性黑色素瘤甲基化等级的能力及其与临床病理特征和生存期的关系：InterMEL是一项回顾性病例对照研究，收集了1998年至2015年期间在美国和澳大利亚确诊的美国癌症联合委员会（AJCC）第8版II期和III期原发性皮肤黑色素瘤患者。病例是指在最初确诊后 5 年内死于黑色素瘤的患者。对照组存活时间超过 5 年，无黑色素瘤复发或复发迹象。通过对 850K 甲基化数据进行共识聚类来区分甲基化类别，并对其临床病理特征、5 年生存状况和不同的甲基化基因组进行评估：在 422 例 InterMEL 黑色素瘤中，共识聚类发现了三种主要的黑色素瘤甲基化类别（MethylClasses）：CpG 岛甲基化表型（CIMP）类别、中间甲基化（IM）类别和低甲基化（LM）类别。与 LM 相比，CIMP 和 IM 与较高的 AJCC 分期（均为 P = .002）、布瑞斯洛厚度（CIMP P = .002；IM P = .006）和有丝分裂指数（均为 P < .001）相关，而 IM 的 N 分期高于 CIMP（P = .01 ）和 LM（P = .007）。在调整了年龄、性别、对数布瑞斯罗厚度、溃疡、有丝分裂指数和 N 分期的多变量模型中，CIMP 和 IM 5 年死于黑色素瘤的可能性比 LM 高 2 倍（CIMP 比值比 [OR]，2.16 [95% CI，1.18 至 3.96]；IM 比值比 [OR]，2.00 [95% CI，1.12 至 3.58]）。尽管CIMP的CpG岛超甲基化更为广泛，但与LM相比，CIMP和IM具有相似的差异甲基化和基因组富集模式：黑色素瘤甲基化类别在预测原发性黑色素瘤患者5年内死于黑色素瘤方面可能具有临床价值，而不受其他临床病理因素的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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