Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
Department of Dermatology, University of North Carolina, Chapel Hill, NC.
JCO Precis Oncol. 2024 Nov;8:e2400375. doi: 10.1200/PO-24-00375. Epub 2024 Nov 7.
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.
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.
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 = .002), Breslow thickness (CIMP = .002; IM = .006), and mitotic index (both < .001) compared with LM, while IM had higher N stage than CIMP ( = .01) and LM ( = .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.
Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.
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类别的能力及其与临床病理特征和生存的关系。
InterMEL 是一项回顾性病例对照研究，在美国和澳大利亚收集了 1998 年至 2015 年间被诊断为第 8 版 AJCC Ⅱ期和Ⅲ期的患者的原发性皮肤黑色素瘤。病例是指在最初诊断后 5 年内死于黑色素瘤的患者。对照组在无黑色素瘤复发或转移的情况下存活超过 5 年。通过对 850K 甲基化数据的一致性聚类，确定了 3 种原发性黑色素瘤甲基化类（MethylClass）：CpG 岛甲基化表型（CIMP）类、中间甲基化（IM）类和低甲基化（LM）类。CIMP 和 IM 与较高的 AJCC 分期（均为 P <.002）、Breslow 厚度（CIMP 为 P <.002；IM 为 P <.006）和有丝分裂指数（均为 P <.001）相关，而与 LM 相比，而 IM 比 CIMP（P <.01）和 LM（P <.007）具有更高的 N 期。在调整年龄、性别、对数 Breslow 厚度、溃疡、有丝分裂指数和 N 期的多变量模型中，CIMP 和 IM 发生黑色素瘤相关 5 年死亡的可能性是 LM 的 2 倍（CIMP 比值比 [OR]，2.16 [95%置信区间，1.18 至 3.96]；IM OR，2.00 [95%置信区间，1.12 至 3.58]）。尽管 CIMP 中有更多的 CpG 岛过度甲基化，但 CIMP 和 IM 与 LM 相比，其差异甲基化和基因集富集模式相似。
在黑色素瘤患者中，黑色素瘤甲基类别的存在可能与其他临床病理因素无关，有助于预测黑色素瘤相关的 5 年死亡率。
