Characterizing the genomic landscape of Langerhans cell histiocytosis using the AACR Project GENIE database.

6572 Background: Langerhans cell histiocytosis (LCH) is a rare neoplasm characterized by the abnormal clonal proliferation of bone marrow-derived Langerhans cells and occurs predominantly in pediatric patients. Clinical manifestations range from localized bone lesions to multisystem involvement. Given the high frequency of MAPK pathway mutations, particularly BRAF V600E, next-generation sequencing is recommended for LCH patients to identify actionable targets. This study utilizes the American Association for Cancer Research (AACR) Project Genomic Evidence Neoplasia Information Exchange (GENIE) database to address existing gaps in the genomic profiling of LCH, aiming to inform long-term risk stratification, uncover prognostic markers, and guide avenues for targeted therapy. Methods: AACR Project GENIE was accessed via cBioPortal (v18.0-public) on November 18, 2025 to identify all LCH patients. Gene mutations and demographic variables were tabulated, and statistical correlations were assessed using two-sided t-tests and non-parametric analyses with Benjamini–Hochberg false discovery rate correction. Entries with unknown values were excluded from analysis; discrepancies in percentage reflect unreported data. Results: This study identified 326 LCH samples from 290 patients, of whom 140 (48.3%) were female and 139 (47.9%) were male. By race, 140 (48.3%) identified as White, 9 (3.1%) as Black, and 9 (3.1%) as Asian. Of the samples, 152 (46.6%) originated from primary tumors and 20 (6.1%) were from metastatic tumors. The cohort included samples from 113 pediatric patients (34.7%) and 212 (65.0%) adults. Frequent mutations included BRAF (n=126; 38.7%), MAP2K1 (n=57; 17.5%), TET2 (n=17; 5.2%), and FAT1 (n=8; 2.5%). No significant difference was identified between the genomic profiles of males and females (p>0.05), although comparisons by race revealed several unique somatic point mutations in Asian and Black patients. Among Asian patients, mutations in MUTYH , PDGFRB , and TERT were significantly enriched, while BORCS8-MEF2B , BRCA1 , and DDR2 mutations were enriched in Black patients. Within this cohort, pediatric patients were more likely to present with PTEN mutations, while adults ≥34 years old were more likely to have VTI1A or ATM mutations. BRAF mutations were mutually exclusive with MAP2K1 mutations (n=124/124; p<0.001), while TET2 mutations frequently co-occurred with ASXL1 mutations (n=2/18, p<0.05). There were no significant differences in mutations between primary and metastatic samples (p>0.05). Conclusions: Our findings support the classification of BRAF and MAP2K1 mutations as key driver mutations and identify several additional mutations that are significantly enriched across demographic groups. Further research into these genomic associations is crucial to address existing knowledge gaps and translate into novel treatment modalities for patients with LCH.