Characterization of Germline and Somatic Genetic Variants in Langerhans Cell Histiocytosis Pathogenesis

/ABSTRACT Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate. The median age at diagnosis is 30 months, and upfront chemotherapy fails in ~50% of patients resulting in multiple relapse events for 40-50% of cases and disease progression associated with potentially fatal progressive neurodegeneration (LCH-ND). Sequencing studies in small cohorts have described >50 somatic mutations in >30 genes in non-MAPK and MAPK pathways, with activating mutations in MAPK pathway genes identified in ~80% of LCH lesions, including BRAFV600E in 45- 65%. However, a driver somatic mutation goes unidentified in ~20% of LCH tumors. There is a “Misguided Myelomonocytic Precursor Model” in which persistence of disease reservoir as well as cell of origin determine extent of disease and clinical risks. However, this model does not address inherited germline genetic effects in LCH. Therefore, we conducted the first genome-wide association study of LCH and identified a SMAD6 variant associated with increased risk. Growing evidence suggests that other germline components like de novo mutations (DNMs) may contribute to a substantial portion of the heritability in complex genetic diseases not detected using GWAS methodology. DNMs play a role in childhood immune dysfunction disorders and genetic syndromes due to mutations in BRAF providing evidence DNMs may also contribute to LCH risk. These findings, in conjunction with our GWAS, support the investigation proposed herein to more clearly define germline genetic effects on LCH risk and adverse LCH outcomes. A critical initiative of this funding mechanism is to analyze large- scale genomic sequence data from pediatric cancer case-parent trios generated through the Gabriella Miller Kids First (GMKF) Research Program. Therefore, the objectives of this R03 application are to identify germline components associated with LCH risk and genomic regions associated with LCH somatic mutational profiles and adverse outcomes using data from 191 case-parent trios sequenced by GMKF. Our central hypothesis is that germline and somatic genetic effects impact LCH pathogenesis and ultimately treatment response. To test this hypothesis, we will: 1) perform a secondary analysis of germline WGS data generated from 191 LCH case-parent trios to more fully elucidate the impact of germline genomic factors, including patterns of inheritance and the role of DNMs, in LCH; and 2) determine LCH germline prognostic markers by leveraging paired germline WGS tumor WES data to test the association between germline variation in key pathways (e.g., TGF-β, BMP, SMAD) and the most common somatic mutational profiles (e.g., BRAFV600E, MAP2K1) in 109 cases with paired data available for assessment. We will also explore whether identified germline variation is associated with i) time to first relapse/disease progression event or ii) time to first LCH-ND event. Successful completion of the proposed aims may (1) improve genetic risk prediction for patients who develop LCH, (2) identify novel therapeutic targets for LCH, and (3) uncover novel mechanisms that may inform the pathogenesis of other MAPK-driven malignancies. Project Number: 1R03CA304855-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Erin Peckham-Gregory (+1 co-PI) | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $321,000 | Activity Code: R03 | Study Section: Special Emphasis Panel[ZRG1 BTC-T (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371027