Abstract 3127: To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH)

Abstract

Abstract a. Introduction : Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations of several genes in the MAPKinase pathway. The cell of origin is a white blood cell known as a dendritic cell priviously called as histiocyte characterized by a unique cytoplasmic organelle, the Birbeck granule, and the expression of CD1a and class II major histocompatibility complex molecules . The mutations cause these dendritic cells to attract other white blood cells and cause a “lesion” in any organ of the body. LCH has multi-orgnan involvement affecting skin bones, lymph nodes, brain etc. Systemic symptoms may include fever, bone pain, weight loss, jaundice, diabetes insipidus. b. Description: LCH is a rare sporadic, non-hereditary and non-malignant disease with unknown etiology characterized with a clonal proliferation of pathologic cells.Recent discovery of recurrent somatic mutations, BRAFV600E in MAPK pathway genes at critical stages of myeloid hematopoietic differentiation in LCH patients supports redefinition of the disease as a myeloproliferative disorder and provides opportunities to develop novel approaches to diagnosis and therapy. In the present proposal, we intend to analyze the BRAFV600E status along with other co-occurring mutations in a cohort of pediatric LCH patients by DNA sequencing in bone marrow samples or Peripheral Blood. Additionally we approach the above unanswered questions by applying an improved machine learning approach for classification and defining an algorithm for disease into different clusters for immediate clinical implication and to address its clinical heterogeneity. c. Results : We screened about 5 LCH patients and performed tageted exome seq to asertain the mutational profile of these patients. Sequencing detected BRAF V600E mutation in 3 of 5 samples for a mutation frequency of 60%. IHC based immunofloroscence shows that the intensity of phospho-MEK and phospho-ERK staining shows no significant alterations samples with mutation in BRAF. We are currently investigating mutations in other members of MAK pathways d. Conclusion : BRAF-V600E mutations were detected in few of our LCH patients. Neverless seeing the disease heterogeneity, we expect additionall mutations. More studies are needed to investigate mutations in the MAPK pathways that could efffect the course of disease management.We further plan to integrate the clinical and genomic findings to design a predictive model for the disease outcome. Citation Format: Subhradip Karmakar, R Dhar, K Purkayastha, R Seth, S Karmakar. To investigate the role of BRAF V600E co-occurring mutations in Langerhans cell histiocytosis (LCH) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3127.