Tesi Michelangelo, Pegoraro Francesco, Peyronel Francesco, Emile Jean-François, Catamerò Francesco, Koster Matthew J, Goyal Gaurav, Collin Matthew, Milne Paul, Boussouar Samia, Cohen-Aubart Fleur, Papo Matthias, Amoura Zahir, Estrada-Veras Juvianee I, O'Brien Kevin, Razanamahery Jerome, Goulabchand Radjiv, Idbaih Ahmed, de Menthon Mathilde, Gensous Noemie, Aouba Achille, Ledoult Emmanuel, Le Scornet Tanguy, Néel Antoine, Go Ronald S, Mazor Roei D, Campochiaro Corrado, Dagna Lorenzo, Diamond Eli L, Vaglio Augusto, Haroche Julien
Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, Firenze, Italy.
Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy.
Leukemia. 2025 May 28. doi: 10.1038/s41375-025-02656-w.
Erdheim-Chester disease (ECD) is a clonal-inflammatory neoplasm driven by mutations in MAPK pathway proto-oncogenes, such as BRAF. Clinical manifestations are protean, affecting virtually every system. This cohort study analyzed 661 patients with ECD to classify them based on clinical features and mutational profiles using unsupervised clustering. Nineteen clinical and mutational variables were subjected to hierarchical clustering combined with k-means. A three-cluster model emerged as the most stable. Most patients were classified according to key features, namely BRAF mutation, and large-vessel, heart, and perirenal involvement. The "Widespread Disease" (WID) cluster (320 patients, 49%) was associated with the presence of the key features and the "Limited Disease" (LIM) cluster (282 patients, 42%) was associated with their absence. The "MAP2K1-RDD" cluster (MAP) was assigned 59 patients (9%), based on MAP2K1 mutation and/or overlapping Rosai-Dorfman-Destombes disease (RDD). Survival analysis revealed worse outcomes for WID compared to LIM (hazard ratio 1.54, 95% CI 1.09-2.17), while no significant survival difference was found for MAP. The identification of these clusters, based on mutational profiles, organ involvement and overlapping conditions, offers a data-driven validation of established clinical observations. These findings substantiate the role of the somatic mutation type in shaping the ECD phenotype.
Erdheim-Chester病（ECD）是一种由MAPK途径原癌基因（如BRAF）突变驱动的克隆性炎症性肿瘤。其临床表现多样，几乎累及每个系统。这项队列研究分析了661例ECD患者，通过无监督聚类根据临床特征和突变谱对他们进行分类。将19个临床和突变变量进行层次聚类并结合k均值聚类。出现了一个三聚类模型，是最稳定的。大多数患者根据关键特征进行分类，即BRAF突变以及大血管、心脏和肾周受累情况。“广泛疾病”（WID）聚类（320例患者，49%）与关键特征的存在相关，“局限性疾病”（LIM）聚类（282例患者，42%）与关键特征的缺失相关。“MAP2K1-RDD”聚类（MAP）有59例患者（9%），基于MAP2K1突变和/或重叠的Rosai-Dorfman-Destombes病（RDD）。生存分析显示，WID组的预后比LIM组差（风险比1.54，95%置信区间1.09 - 2.17），而MAP组未发现显著的生存差异。基于突变谱、器官受累情况和重叠病症对这些聚类的识别，为已有的临床观察提供了数据驱动的验证。这些发现证实了体细胞突变类型在塑造ECD表型中的作用。
