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

Abstract

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 approximately 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 SS-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival (EFS) in the overall cohort, neither BRAF nor MAP2K1 mutations associated with EFS 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.

Molecular and clinicopathologic characterization of pediatric histiocytoses

“…In the present study, BRAF V600E was found in 45.1% of all histiocytoses and in 50.3% of childhood LCH. This result is in accordance with previously published findings showing BRAF V600E in 19%–67.6% of pediatric LCH 3–6 . In four children with LCH in the current study, we observed more complex alterations (small deletion/duplication) around codon V600 (Supplementary Table 1).…”

“…Furthermore, we identified MAP2K1 alterations in 20% of RDD cases and in one patient with JXG. Previous publications have reported MAP2K1 mutations in 11%–30% of pediatric LCH patients 5–7 and more rarely in other histiocytosis types 8,12,35,36 . Because non‐ BRAF V600E ‐mutated LCH cases constitute half of our LCH cohort, we can estimate that MAP2K1 mutations are found in 21% of childhood LCH, in accordance with previously published data.…”

“…Others have reported similar findings for pediatric LCH, in part, but in smaller cohorts 4,37,44 . One exception is a recently published international cohort study by Kemps et al, which included an equivalent number of patients to ours 5 . Regarding these data for children diagnosed with BRAF V600E ‐mutated LCH, specific attention should be paid to young children regarding MS‐RO+ LCH risk.…”

“…For this L group, the mutational spectrum is the best described, and molecular alterations involving the MAP‐kinase pathway are assumed to be identifiable in about three of every four cases. In childhood LCH, BRAF V600E is the most frequently identified mutation (about 50%), followed by alterations in exons 2 and 3 of MAP2K1 , which are found in ~11%–30% of pediatric cases 3–8 . Recently, small deletions and duplications of BRAF exon 12 have been reported, but their prevalence is less clearly established 9,10 .…”

“…In childhood LCH, BRAF V600E is the most frequently identified mutation (about 50%), followed by alterations in exons 2 and 3 of MAP2K1, which are found in $11%-30% of pediatric cases. [3][4][5][6][7][8] Recently, small deletions and duplications of BRAF exon 12 have been reported, but their prevalence is less clearly established. 9,10 Data are even more scarce for the mutational spectrum of less frequent histiocytoses such as juvenile xanthogranuloma (JXG), Rosai-Dorfman disease (RDD), and malignant histiocytosis (MH).…”