Abstract B073: Leveraging genomic diversity identifies additional germline risk loci in SMAD6 for Langerhans cell histiocytosis

Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate with recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions; how...

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Veröffentlicht in:Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2023-12, Vol.32 (12_Supplement), p.B073-B073
Hauptverfasser: Shetty, Priya B., Peckham-Gregory, Erin, Stricker, Erik, Lin, Howard, Scull, Brooks, Ehli, Erik, Davis, Christel, McClain, Kenneth, Lupo, Philip, Allen, Carl, Scheurer, Michael
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Sprache:eng
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Zusammenfassung:Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate with recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions; however, germline risk factors remain largely unknown. A SEER analysis reported that incidence of high-risk LCH was higher in Hispanic populations than non-Hispanic populations, and lowest in non-Hispanic Black populations. Our group reported that Hispanic mothers/couples were more likely to have children with LCH compared to non-Hispanic white mothers/couples. In the first GWAS of LCH, our group identified and validated a risk variant in SMAD6 associated with a 3-fold increase in risk. Our current objective is to leverage the genomic diversity of our patient population to identify additional SMAD6 LCH risk loci. Methods: Cases diagnosed with LCH were recruited at Texas Children’s Hospital (n=466). Targeted sequencing of SMAD6 was conducted among cases with ~200x coverage at the Avera Institute of Human Genetics. We accessed aggregate-level SMAD6 sequence data in SMAD6 from a median of 15,694 non-cancer controls in gnomAD v2.1.1. Fisher’s exact test was applied to 154 SMAD6 variants (Bonferroni critical P-value of 3.2 x 10-4) to assess association between SMAD6 variation and case status. Analyses were conducted with SAS and population genetics were assessed in Ensembl. Results: In this case-control analysis, 49 variants were significantly associated with LCH risk, including our previous risk locus. Leveraging population genetics, we found that the top 4 SNPs have low MAF globally (range 2-9%) but are enriched (MAF range 15-23%) in Hispanic/Latinx populations (MXL, CLM, PEL). The top two hits are in high LD in some of the Hispanic/Latinx and Black (ASW) populations (r2: MXL= 0.71, ASW = 1.0, PEL = 0.92), but not globally. The third SNP is in high LD with the peak SNP in these populations, as well (r2: MXL= 0.28, ASW = 0.83, PEL = 0.51). The fourth hit, which is our previously identified risk locus, has moderate LD with the peak SNP in Hispanic/Latinx populations (r2: MXL= 0.31, CLM = 0.3, PEL = 0.13). Conversely, the LD between the 1st and 5th SNPs was low globally and within different populations. Conclusion: We identified additional support for the role of SMAD6 variation in LCH susceptibility across and within diverse ancestral populations. These findings suggest
ISSN:1538-7755
1538-7755
DOI:10.1158/1538-7755.DISP23-B073