Molecular Epidemiology of Langerhans Cell Histiocytosis: Evaluating the Impact of SMAD6 and Genetic Ancestry on Disease Risk

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PROJECT SUMMARY/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 up-front chemotherapy fails in ~50% of patients resulting in multiple relapse events for 40-50% of cases, and long-term sequelae. Sequencing studies have found recurrent, mutually exclusive somatic activat- ing mutations in MAPK pathway genes in ~85% of LCH lesions, including BRAF V600E in 50-65%. There is a “Misguided Myelomonocytic Dendritic Cell Precursor Model” in which specific somatic MAPK mutations at criti- cal stages of myeloid differentiation determine extent of disease. However, this model fails to explain the signif- icant differences in LCH risk across ethnicities. Despite advances to elucidate the somatic mutational land- scape underlying LCH pathogenesis, germline risk factors remain largely unknown. Therefore, we conducted the first genome-wide association study of LCH and identified a SMAD6 variant associated with increased risk. SMAD6 inhibits bone morphogenetic protein and transforming growth factor-beta/activin signaling, which are determinants of Langerhans cell differentiation. This variant appears to suppress SMAD6 protein expression without a decrease in SMAD6 messenger RNA expression in patients carrying the risk allele. This risk allele is also more common in Hispanics who are at the highest risk of LCH, and absent in blacks who experience the lowest LCH incidence. Our preliminary data also support the emerging observation that LCH somatic activating mutations vary by race/ethnicity. Specifically, sequencing of tumors from black patients indicated that only 25% were BRAF V600E+ (compared to >60% in other populations), whereas 50% had mutations in MAP2K1 (com- pared to <10% in other populations). Therefore, the objectives of the current study are to characterize the role of SMAD6 on LCH susceptibility and identify germline genomic regions associated with LCH somatic mu- tations. The central hypotheses are: (1) causal genetic variant(s) in SMAD6 underlie susceptibility to LCH, and (2) differences in LCH somatic activating mutations by race/ethnicity are related to Native American ge- netic ancestry. We will utilize the Childhood Cancer Research Network (CCRN) and the newly opened registra- tion and biobanking protocol, Project:EveryChild, to recruit 600 LCH case-parent trios through the Children’s Oncology Group (COG). We will also work with our collaborators worldwide to assemble a cohort of an addi- tional 400 LCH cases. The specific aims are to: 1) systematically evaluate inherited and de novo SMAD6 ge- netic variation and identify novel loci for LCH susceptibility using 600 case-parent trios; 2) characterize the function of germline variation in SMAD6 on LCH pathogenesis; and 3) identify the role of the germline genome on LCH somatic mutations using admixture mapping in a multi-ethnic cohort of 1,000 cases. Successful com- pletion of the proposed aims may (1) improve genetic testing and counseling strategies in LCH patients and families; (2) advance surveillance and chemoprevention protocols; and (3) identify novel therapeutic targets.