Clinical associations of BRAF and MAP2K1 mutations in pediatric Langerhans cell histiocytosis: When 1 + 1 = 3

With great interest, we have read the recent publication by Hélias-Rodzewicz and colleagues describing the molecular and clinicopathologic characterization of 415 children with histiocytoses included in the French national histiocytosis registry, including 366 with Langerhans cell histiocytosis (LCH).1 Among LCH patients, the authors detected somatic BRAFV600E mutations in 184 cases, MAP2K1 exon 2 or 3 mutations in 44 cases, BRAF exon 12 deletions in 26 cases, and BRAF exon 12 insertions in 8 cases. Because the groups of patients with MAP2K1 or BRAF exon 12 alterations encompassed fewer than 50 patients each, the authors stated that the analysis of clinical correlations of these non-BRAFV600E mutations was limited. Although it is certainly possible to gain valuable insights from <50 patients, as illustrated by our recent collaborative study of 39 cases with ALK-positive histiocytosis,2 we agree with the French authors that larger groups of patients are required to draw more definitive conclusions regarding the clinical impact of recurrent driver mutations beyond BRAFV600E. Prior to publication of the study by Hélias-Rodzewicz et al, we reported the findings of an international clinicogenomic study of childhood LCH,3 which did not involve French patients. We described detailed clinical characteristics and outcomes of 377 children with LCH, including 191 with BRAFV600E, 54 with MAP2K1 exon 2 or 3 mutations, 27 with BRAF exon 12 deletions, and 12 with BRAF exon 12 insertions. Combining our findings with those from the separate study by Hélias-Rodzewicz et al. provides us the unprecedented opportunity to explore the clinical features of >50 patients with MAP2K1 mutations or BRAF exon 12 deletions — the second and third most common oncogenic drivers of pediatric LCH.4 Combining the two study cohorts yielded a virtual cohort of 743 children with LCH genotyped for at least BRAFV600E. BRAFV600E was detected in 375/743 (50.5%) patients, with very similar frequencies in both studies (50.3%1 vs. 50.7%3). Among patients without BRAFV600E, MAP2K1 exon 2 or 3 mutations were detected in 98 cases, BRAF exon 12 deletions in 53 cases, BRAF exon 12 insertions in 20 cases, and BRAF exon 15 mutations other than BRAFV600E in 14 cases (Tables S1–S3). As convincingly demonstrated previously,1, 3, 5 BRAFV600E is strongly associated with multisystem disease (Figure 1A,B), particularly with involvement of risk organs (liver, spleen, and/or hematopoietic system). Yet, children with this severe disease presentation occasionally had alternative BRAF or MAP2K1 alterations (Figure S1). In addition, BRAFV600E is strongly associated with skin involvement (Figure 1D). In contrast, MAP2K1 mutations were associated with a higher incidence of bone involvement (Figure 1C), whereas BRAF exon 12 deletions appeared to correlate with more lung involvement (Figure 1E), substantiating our previous observations.3 No significant differences in lymph node, pituitary, or (non-pituitary) central nervous system (CNS) involvement were observed (Figure 1F,G; Table S1), although this may be caused by a lack of power. Notably, 19/19 patients who developed neurodegenerative LCH had BRAFV600E (Table S1), underscoring the intimate relation between BRAFV600E and this devastating clinical condition.6 Moreover, patients with BRAFV600E received second-line treatment and targeted therapy more frequently than patients with BRAF exon 12 or MAP2K1 mutations (Table S1). However, these outcome data should be interpreted with caution, as we previously showed that this seems (primarily) driven by the association of BRAFV600E with disease extents known for high rates of progression or relapse, including multisystem LCH and single-system multifocal skin disease.3 In conclusion, by combining published data from two large cohort studies of pediatric LCH, we present a concise overview of the clinical impact of somatic BRAF or MAP2K1 mutations on LCH presentation during childhood. Although the individual studies convincingly showed the frequency and clinical associations of BRAFV600E, the combination of their results allowed a first look into the clinical presentation of >50 children with LCH harboring BRAF exon 12 deletions or MAP2K1 mutations. In the setting of a rare disease like LCH, the combination of research data is often crucial and synergistic. Increasing international collaboration through the Histiocyte Society, the European Consortium for Histiocytosis (ECHO), and the North American Consortium for Histiocytosis (NACHO), as well as prospective molecular analysis of LCH lesions, will further advance our understanding of the pathogenesis of this clinically heterogeneous disorder. Paul G. Kemps analyzed the combined clinicogenomic data, prepared the figures and tables, and drafted the manuscript. Cor van den Bos and Astrid G. S. van Halteren were co-PI's of the original study by Kemps et al.3 and revised the manuscript. We thank all the authors who were involved in our international collaborative study of childhood LCH for their contributions.3 We thank Lieke Feijen (Princess Máxima Center for Pediatric Oncology) for statistical advice. The original study performed by Kemps et al. was financially supported by the Histiocytosis Association and the 1000 Kaarsjes voor Juultje Foundation. Paul G. Kemps received a M.D./Ph.D. grant from Leiden University Medical Center. The authors declare no competing interests. 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 Greenwood, Karel Svojgr, Auke Beishuizen, Jan A. M. van Laar, Ulrike Pötschger, Caroline Hutter, Elena Sieni, Milen Minkov, Oussama Abla, Tom van Wezel. Data are available from the corresponding author upon reasonable request. Figure S1. Disease extent by mutation subtype. Figure S2. Main figure with all p values. Table S1. Clinical features and outcomes by mutation subtype. Table S2. Clinical features and outcomes of patients with BRAFV600E, MAP2K1, or BRAF exon 12 mutations from the study by Kemps et al. Table S3. Clinical features and outcomes of patients with BRAFV600E, MAP2K1, or BRAF exon 12 mutations from the study by Hélias-Rodzewicz et al. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.