&lt;i&gt;BRAF&lt;/i&gt; V600E-positive cells as molecular markers of bone marrow disease in pediatric Langerhans cell histiocytosis

Kudo, Ko; Toki, Tsutomu; Kanezaki, Rika; Tanaka, Tatsuhiko; Kamio, Takeshi; Sato, Toshio; Sasaki, Susumu; Imamura, Masatoshi; Imai, Chihaya; Ando, Kenji; Kakuda, Harumi; Doi, Takehiko; Kawaguchi, Hiroshi; Irie, Masahiro; Sasahara, Yoji; Tamura, Akihiro; Hasegawa, Daiichiro; Itakura, Yosuke; Watanabe, Kenichiro; Sakamoto, Kenichi; Shibata, Yoko; Kato, Motohiro; Kudo, Kazuko; Fukano, Reiji; Satō, Atsushi; Yagasaki, Hiroshi; Kanegane, Hirokazu; Kato, Itaru; Umeda, Katsutsugu; Adachi, Souichi; Kataoka, Tatsuki R.; Kurose, Akira; Nakazawa, Atsuko; Terui, Kiminori; Ito, Etsuro

doi:10.3324/haematol.2021.279857

Cited by 8 publications

(5 citation statements)

References 15 publications

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“…To this end, (longitudinal) assessment of mutant alleles in cellular or cell-free DNA derived from peripheral blood and/or bone marrow represents an interesting opportunity for prognostic staging and monitoring response to therapy. 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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“…Both his neurological symptoms and radiological findings improved spontaneously (Figure 2B). Droplet digital polymerase chain reaction and next‐generation sequence analyses of FFPE samples 8,9 failed to detect the somatic mutations frequently found in histiocytic neoplasms, including BRAF, MAP2K1, KRAS, NRAS, CSF1R, and ALK.…”

Section: Case Reportmentioning

confidence: 99%

Juvenile xanthogranuloma manifesting with LCH‐associated neurodegenerative disease‐like radiological findings

Daifu,

Umeda,

Yokoyama

et al. 2024

Pediatric Blood & Cancer

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Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)‐associated neurodegenerative disease (ND)‐like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH‐oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG‐associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions.

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“…Multiple studies have shown that LCH is an inflammatory myeloid neoplasm in which genetic aberrancies are acquired in early hematopoietic progenitors and present along their differentiation into mononuclear dendritic/ histiocytic cells. [26][27][28] BRAF V600E mutations have been identified in approximately 50% of all LCH cases, and MAP2K1 mutations are the main genetic driver alterations in BRAF-wild type LCH, 29,30 both of which cause continuous activation of the RAS-RAF-MAPK-ERK pathway and result in proliferation, apoptosis defects, and inflammation dysregulation. 27 Interestingly, Xerri et al 31 performed array-comparative genomic hybridization and targeted next-generation sequencing studies on several patients with morphological features of Langerhans cell sarcoma (LCS) and reported a somatic homozygous loss affecting the CDKN2A/B locus and somatic NOTCH1 mutations in LCS cases but not in the control LCH cases.…”

Section: Lchmentioning

confidence: 99%

“…[26][27][28] BRAF V600E mutations have been identified in approximately 50% of all LCH cases, and MAP2K1 mutations are the main genetic driver alterations in BRAF-wild type LCH, 29,30 both of which cause continuous activation of the RAS-RAF-MAPK-ERK pathway and result in proliferation, apoptosis defects, and inflammation dysregulation. 27 Interestingly, Xerri et al 31 performed array-comparative genomic hybridization and targeted next-generation sequencing studies on several patients with morphological features of Langerhans cell sarcoma (LCS) and reported a somatic homozygous loss affecting the CDKN2A/B locus and somatic NOTCH1 mutations in LCS cases but not in the control LCH cases. Previous studies revealed that the Notch ligand, its receptor, and Notch activation contribute to the pathogenesis of Langerhans cell neoplasms.…”

Section: Lchmentioning

confidence: 99%

“…25 Recent studies suggest that bone marrow involvement (detection of BRAF V600E mutation by allele-specific droplet digital polymerase chain reaction or the presence of atypical LCH cells identified by flow cytometry) may indicate a higher risk for disease progression. 27,37 Treatment options for LCH include the following: topical steroids, nitrogen mustard, and imiquimod; surgical resection of isolated lesions; phototherapy; and systemic methotrexate, 6-mercaptopurine, vinblastine/vincristine, thalidomide, cladribine, and/or cytarabine. 25 The detailed treatment protocols have been well summarized in the literature.…”

Section: Lchmentioning

confidence: 99%

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Pediatric Histiocytic Disorders: Morphology, Immunophenotype and Genetics

Cheng,

Zhu,

Pan

et al. 2023

J Clin Transl Pathol

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Histiocytic disorders are rare in childhood and often present with a wide spectrum of histological and clinical symptoms, making their diagnosis challenging. The pathological classification of histiocytic disorders has been evolving during the last few decades, and new diagnostic criteria and classifications have been recently updated. Herein, we review pediatric histiocytic disorders, focusing on the pathological features of morphology, immunophenotype, and newly discovered molecular data. These insights shed light on the pathogenesis of these disorders and may become therapeutic biomarkers.

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<i>BRAF</i> V600E-positive cells as molecular markers of bone marrow disease in pediatric Langerhans cell histiocytosis

Abstract: Not available.

Cited by 8 publications

References 15 publications

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

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

Juvenile xanthogranuloma manifesting with LCH‐associated neurodegenerative disease‐like radiological findings

Pediatric Histiocytic Disorders: Morphology, Immunophenotype and Genetics

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