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BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases
Khaled Alayed1, L Jeffrey Medeiros2, Keyur P Patel2
1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030; Department of Pathology, King Saud University, Riyadh, 11461, Saudi Arabia.
Insights
This study found MAP2K1 mutations in BRAF-negative Langerhans cell histiocytosis (LCH) cases. BRAF mutations were less common in adults than children, with high concordance between genetic and protein analysis.
Area of Science:
- Genetics
- Oncology
- Pathology
Background:
- Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of Langerhans cells.
- BRAF mutations, particularly V600E, are frequently identified in LCH.
- Recent research suggests MAP2K1 mutations may occur in BRAF-negative LCH cases.
Purpose of the Study:
- To investigate the frequency of BRAF and MAP2K1 mutations in a cohort of LCH patients.
- To compare the prevalence of BRAF mutations in adult LCH patients with previously reported pediatric data.
- To assess the correlation between mutations and clinical parameters.
Main Methods:
- Fifty LCH cases were analyzed for BRAF mutations using molecular methods.
- A subset of BRAF-negative cases underwent analysis for MAP2K1 mutations.
- Immunohistochemical analysis was performed for BRAF mutation confirmation.
Main Results:
- BRAF V600E mutation was detected in 16% of cases.
- MAP2K1 mutations were found in 46% of BRAF-negative cases.
- Patients with BRAF mutations were significantly younger than those with wild-type BRAF.
Conclusions:
- MAP2K1 mutations are frequent in BRAF-negative LCH, particularly in adult patients.
- The lower overall BRAF mutation frequency in this adult cohort warrants further investigation.
- High concordance between mutational and immunohistochemical BRAF analysis was observed.
Abstract:
Langerhans cell histiocytosis (LCH) is a proliferation of Langerhans cells, often associated with lymphocytes, eosinophils, macrophages, and giant cells. BRAF mutations, usually V600E, have been reported in 40%-70% of cases, and recently, MAP2K1 mutations have been reported in BRAF-negative cases. We assessed 50 cases of LCH for BRAF mutations and assessed a subset of cases for MAP2K1 mutations. The study group included 28 men and 22 women (median age, 36.5 years; range, 1-78 years). BRAF V600E mutation was detected in 8 (16%) cases including 3 (30%) skin, 2 (11%) bone, 1 (50%) colon, 1 (20%) lung, and 1 (33%) extradural, intracranial mass. MAP2K1 mutations were detected in 6 of 13 (46%) BRAF-negative cases including 2 (100%) lymph node, 2 (50%) bone, 1 (25%) skin, and 1 (100%) orbit. Patients with BRAF mutation were younger than patients with wild-type BRAF (median age, 28 versus 38 years; P = .026). The median age of MAP2K1-mutated patients was 34.5 years, similar to patients without MAP2K1 mutation (41 years; P = .368). In agreement with 2 recent studies, we showed a high frequency of MAP2K1 mutations in BRAF-negative LCH cases. Unlike other studies, the overall frequency of BRAF mutation in this cohort is substantially lower than what has been reported in pediatric patients, perhaps because most patients in this study were adults. Moreover, we showed a high concordance between mutational and immunohistochemical analysis for BRAF mutation. There was no statistically significant association between BRAF or MAP2K1 mutation and anatomic site, unifocal versus multifocal presentation, or clinical outcome.
