Molecular and clinicopathologic characterization of pediatric histiocytoses
Zofia Hélias‐Rodzewicz, Jean Donadieu, Nathalie Terrones, Mohamed‐Aziz Barkaoui, Anne Lambilliotte, Despina Moshous, Caroline Thomas, Saba Azarnoush, Marlène Pasquet, L Mansuy, Nathalie Aladjidi, Éric Jeziorski, Perrine Marec‐Bérard, Marion Gilibert‐Yvert, Alexandra Spiegel, Paul Saultier, Isabelle Pellier, Anne Pagnier, Sophie Pertuisel, Maryline Poirée, Damien Bodet, Frédéric Millot, Florentina Isfan, Jean‐Louis Stephan, Amaury Leruste, Charlotte Rigaud, Bruno Filhon, Liana Carausu, Yves Réguerre, Isabelle Kieffer, Bénédicte Brichard, Rim Ben Jannet, Mariama Bakari, Ahmed Idbaïh, Christine Bodemer, Fleur Cohen‐Aubart, Julien Haroche, Abdellatif Tazi, Sabah Boudjemaa, Sylvie Fraitag, Jean‐François Emile, Sébastien Héritier, for the French Histiocytosis Study Group
Abstract
Abstract The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non‐Langerhans cell histiocytosis (‐LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAF V600E . Most BRAF WT samples were analyzed by next‐generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim‐Chester disease, 21 Rosai‐Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAF V600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non‐ BRAF V600E ‐mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 ( n = 44), BRAF exon 12 deletions ( n = 26), and duplications ( n = 8), other BRAF V600 codon mutation ( n = 4), and non‐MAP‐kinase pathway genes ( n = 5). Wild‐type sequences were identified in 17.1% of samples. BRAF V600E was the only variant significantly correlated with critical presentations: organ‐risk involvement and neurodegeneration. MAP‐kinase pathway mutations were identified in seven RDD (mostly MAP2K1 ) and three JXG samples, but most samples were wild‐type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAF G469R mutation. Rarely, we identified mutations unrelated to MAP‐kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.