ASPO Abstracts
Inherited Genetic Effects and Risk of Langerhans Cell Histiocytosis Relapse
Category: Molecular Epidemiology & Environment, Early Detection & Risk Prediction
Conference Year: 2018
Abstract Body:
Purpose: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia. Approximately 50% of LCH patients relapse, and 40% experience a second relapse event within two years. Sequencing studies have found activating mutations in MAPK pathway genes in ~85% of LCH lesions. Notably, carriers of BRAF-V600E experience a 2-fold increased relapse risk. However, the role of inherited genetic effects in LCH relapse remains unknown. Therefore, we conducted a pilot genome-wide association study to determine the association between inherited genetic variants and LCH relapse risk. Methods: LCH cases (n=117) were recruited from Texas Children’s Hospital, consisting of 52 cases who experienced a relapse event and 65 cases without an event. Genotyping was performed on the Illumina Omni5 Quad BeadChip. We evaluated the role of common variants (minor allele frequency >5%) on LCH relapse using PLINK. We applied a genome-wide threshold of P<5.0x10-8, and threshold of suggestive significance at P<1.0x10-5. Results: We identified a variant in high linkage disequilibrium with a cluster of loci on Chromosome 9 that surpassed our threshold of suggestive significance (non-coding RNA LOC100506532 rs2182640; P=6.98x10-6). This intronic variant was associated with decreased risk of LCH relapse after adjusting for age at diagnosis, sex, and the top two principal components (adjusted odds ratio: 0.16; 95% confidence interval: 0.07-0.35). While this non-coding RNA gene is largely uncharacterized, non-coding RNAs function to regulate gene expression at the transcriptional and post-transcriptional level. Conclusion: It is unclear which variant in the LOC100506532 cluster is a potentially causal allele. One of these variants may be a proxy for the causal locus, or may act through an effect on other genes in the same region or at distal sites. Notably RXRA, a retinoic acid receptor, is located in close proximity (~400kb) to LOC100506532 and regulates gene expression in various biologic processes. Risk variants within this gene have been identified in melanoma and colorectal cancers, among other malignancies. While validation of this genomic region in an independent replication set is necessary, our initial results support a role for inherited genetic effects in LCH relapse.
Keywords: Langerhans Cell Histiocytosis Relapse Genome-wide Association Study Molecular Epidemiology