Abstract
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 BRAFV600E 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.
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Data availability
Due to privacy and ethical restrictions, patient-level data cannot be shared publicly. Aggregated or de-identified data may be available upon reasonable request to the corresponding author, subject to institutional and ethical approvals. Code for generating a fake simulated dataset and carrying out the present analysis on it is available at: https://github.com/miki-tesi/ECD-clusters/.
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Acknowledgements
This work was funded in part by the 2021 Annual Grant of the ECD Global Alliance and by the “Current Research Annual Funding” of the Italian Ministry of Health.
Funding
This work was funded in part by the 2021 Annual Grant of the ECD Global Alliance (FP) and by the “Current Research Annual Funding” of the Italian Ministry of Health (AV). It was supported by the National Institutes of Health/National Cancer Institute (P30 CA008748), as well as the National Cancer Institute (R37CA259260; ELD). This was supported by the Frame Family Fund (ELD), the Joy Family West Foundation (ELD), and the Applebaum Foundation (ELD). ELD discloses unpaid editorial support from Pfizer Inc and serves on an advisory board for Opna Bio, all outside the submitted work.
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Tesi M contributed to conceptualization, data collection and curation, study management, statistical analysis, and writing of the manuscript draft, Pegoraro F to conceptualization, data collection and curation, study management, scientific investigation, critical review and editing of the manuscript, Vaglio A to conceptualization, study management, writing of the manuscript draft, scientific investigation and supervision, Haroche J to conceptualization, study management, scientific investigation and supervision, critical review and editing of the manuscript, Peyronel F to conceptualization and scientific investigation, Catamerò F to data collection and curation. Emile JF, Koster MJ, Goyal G, Collin M, Milne P, Boussouar S, Cohen-Aubart F, Papo M, Amoura Z, Estrada-Veras JI, O’Brien K, Razanamahery J, Goulabchand R, Idbaih A, de Menthon M, Gensous N, Aouba A, Ledoult E, Le Scornet T, Néel A, Go RS, Mazor RD, Campochiaro C, Dagna L, Diamond EL contributed by overseeing patient care at their respective institutions, collecting clinical data, and providing it for inclusion in this study.
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This study was approved by the Ethics Committee of Meyer Children’s Hospital IRCCS (approval date: June 9, 2020). All methods were carried out in accordance with relevant guidelines and regulations. Written informed consent was obtained from all participants for inclusion in the study. For participants whose identifiable images are published, written informed consent for publication was also obtained separately.
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Tesi, M., Pegoraro, F., Peyronel, F. et al. Cluster analysis reveals the clinical spectrum of Erdheim-Chester disease. Leukemia 39, 1987–1996 (2025). https://doi.org/10.1038/s41375-025-02656-w
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DOI: https://doi.org/10.1038/s41375-025-02656-w
