Department of Biosciences and Nutrition, Karolinska Institutet, 141 83 Huddinge, Sweden.
Department of Medical and Clinical Genetics, University of Helsinki; Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, 00290 Helsinki, Finland.
Hum Mol Genet. 2023 Mar 20;32(7):1063-1071. doi: 10.1093/hmg/ddac217.
Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.
精准医学在所有肿瘤类型的管理中都具有巨大的潜力。本回顾性研究旨在探究由 MED12 和 HMGA2 基因异常驱动的两种最常见的具有明显遗传差异的子宫肌瘤亚类是否会影响孕激素受体调节剂乌利司他的治疗反应。对 101 例接受乌利司他治疗后手术切除的子宫肌瘤的直径变化和突变状态进行了研究。结果显示，两种主要亚类之间的治疗反应存在显著差异。与 HMGA2 驱动的肌瘤相比，MED12 突变的肌瘤对乌利司他治疗的收缩反应可能性高 4.4 倍（95%置信区间 1.37-13.9；P = 0.013），并且在多变量分析中分子分类是独立的预测因素。这一发现与基因表达和 DNA 甲基化分析结果一致，这些分析结果显示出孕激素受体信号转导的亚类特异性差异。这项工作提供了一个原理性的证据，即子宫肌瘤的治疗反应受到分子分类的影响，在评估当前和未来的子宫肌瘤治疗方法时应考虑遗传亚类。
