Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Paul G. Kemps, Timo C.E. Zondag, Helga B. Arnardóttir, Nienke Solleveld-Westerink, Jelske Borst, Eline C. Steenwijk, Demi van Egmond, Joost F. Swennenhuis, Ellen Stelloo, Irene Trambusti, Robert M. Verdijk, Carel J.M. van Noesel, Arjen H.G. Cleven, Marijn A. Scheijde-Vermeulen, Marco J. Koudijs, Lenka Krsková, Cynthia Hawkins, R. Maarten Egeler, Jesper Brok, Tatiana von Bahr GreenwoodKarel Svojgr, Auke Beishuizen, Jan A.M. van Laar, Ulrike Pötschger, Caroline Hutter, Elena Sieni, Milen Minkov, Oussama Abla, Tom van Wezel, Cor van den Bos*, Astrid G.S. van Halteren*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)
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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ~80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)–risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Original languageEnglish
Article numberPMID: 36083130
Pages (from-to)664-679
Number of pages16
JournalBlood advances
Issue number4
Publication statusPublished - 21 Feb 2023

Bibliographical note

Funding Information:
This study was supported by grants from Histiocytosis Association of America (O.A., C.v.d.B., A.G.S.v.H.), Stichting 1000 Kaarsjes voor Juultje (A.G.S.v.H.), Stichting Kiwanis Run-for-LCH (A.G.S.v.H.), and Histio UK (T.v.W., A.G.S.v.H.).

Funding Information:
P.G.K. received an MD/PhD grant from Leiden University Medical Center.

Publisher Copyright:
© 2023 by The American Society of Hematology.


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