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Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study
PG. Kemps, TCE. Zondag, HB. Arnardóttir, N. Solleveld-Westerink, J. Borst, EC. Steenwijk, D. van Egmond, JF. Swennenhuis, E. Stelloo, I. Trambusti, RM. Verdijk, CJM. van Noesel, AHG. Cleven, MA. Scheijde-Vermeulen, MJ. Koudijs, L. Krsková, C....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
NLK
Directory of Open Access Journals
od 2016
PubMed Central
od 2016
Europe PubMed Central
od 2016
ROAD: Directory of Open Access Scholarly Resources
od 2016
- MeSH
- histiocytóza z Langerhansových buněk * genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- mutace MeSH
- nádory * MeSH
- protoonkogenní proteiny B-raf genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Cergentis BV Utrecht The Netherlands
Department of Immunology Erasmus MC Rotterdam The Netherlands
Department of Internal Medicine Clinical Immunology Erasmus Medical Center Rotterdam The Netherlands
Department of Pathology Amsterdam University Medical Centers Amsterdam The Netherlands
Department of Pathology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands
Department of Pathology Leiden University Medical Center Leiden The Netherlands
Department of Pathology The Hospital for Sick Children University of Toronto Toronto ON Canada
Department of Pathology University Medical Center Groningen Groningen The Netherlands
Department of Pediatric Oncology Sophia Children's Hospital Erasmus MC Rotterdam The Netherlands
Department of Pediatrics Leiden University Medical Center Leiden The Netherlands
Pediatric Hematology Oncology Department Meyer Children's University Hospital Florence Italy
Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
Citace poskytuje Crossref.org
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