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214 Epigenome-Wide Association Study of Acute Lymphoblastic Leukemia in Children with Down Syndrome

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Clinical, genetic and societal risk factors impacting ALL outcomes
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Genomics, Bioinformatics, Diseases, Pediatric, Neonatal, Lymphoid Malignancies, Biological Processes, Genomic Profiling, Technology and Procedures, Study Population
Saturday, December 11, 2021: 2:45 PM

Shaobo Li1*, Pagna Sok, PhD2*, Keren Xu, MPH1*, Ivo S Muskens, PhD1*, Natalina Elliott, PhD3*, Swe Swe Myint1*, Priyatama Pandey, MS1*, Helen M Hansen, BSc4*, Libby M Morimoto, PhD5*, Alice Y Kang, MPH5*, Catherine Metayer, MD, PhD5*, Xiaomei Ma, PhD6*, Beth A Mueller, PhD7*, Anindita Roy, MD, PhD3, Irene Roberts, MD3, Karen R Rabin, MD, PhD2, Austin L Brown, MPH, PhD2*, Philip J. Lupo, Ph.D., M.P.H.2*, Joseph L. Wiemels, PhD1* and Adam J. de Smith, PhD1

1Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA
2Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX
3Department of Paediatrics and MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
4Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
5School of Public Health, University of California Berkeley, Berkeley, CA
6Department of Chronic Disease Epidemiology, Yale University School of Public Health, New Haven, CT
7Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA

Background: Down syndrome (DS) is associated with an up to 30-fold increased risk of B-cell acute lymphoblastic leukemia (ALL), and DS-ALL patients have worse overall survival and increased long-term treatment-related health conditions compared with non-DS ALL patients. In a recent genome-wide association study of DS-ALL, established ALL genetic risk loci were associated with DS-ALL, with several single nucleotide polymorphisms (SNPs) conferring a larger effect on ALL risk in the context of DS than in euploidy. We performed an epigenome-wide association study (EWAS) to elucidate whether epigenetic differences at birth are associated with risk of subsequent DS-ALL.

Methods: The DS-ALL Discovery Study included 147 DS-ALL cases and 198 DS controls from the International Study of Down Syndrome Acute Leukemia, with newborn dried bloodspots (DBS) obtained from California (n=326) and Washington state (n=19) biobanks. The DS-ALL Replication Study included 24 DS-ALL cases and 24 DS controls with newborn DBS from the Michigan Neonatal Biobank. DNA was isolated from DBS, bisulfite converted, and assayed using Illumina Infinium MethylationEPIC Beadchip genome-wide DNA methylation arrays. Raw data were processed using “minfi” and “noob” packages in R. Reference-based deconvolution of blood cell proportions was performed using the Identifying Optimal DNA methylation Libraries (IDOL) algorithm, using DNA methylation data from cord blood reference samples, to estimate proportions of B cells, T cells (CD4+ and CD8+), monocytes, granulocytes, natural killer cells, and nucleated red blood cells. We compared each cell type proportion between DS-ALL cases and DS controls using linear regression adjusting for sex, plate, and principal components (PCs) to account for genetic ancestry. To identify single CpG probes associated with DS-ALL risk, we performed a multiethnic EWAS of DS-ALL in each study using linear regression adjusting for sex, plate, and PCs related to: 1) cell-type proportions and 2) genetic ancestry. Differentially methylated regions (DMRs) were identified using DMRcate and comb-p methods. In the Discovery Study, genome-wide SNP array data were available for 131 cases and 130 controls, and data from targeted sequencing of somatic mutations in exons 2/3 of GATA1 were available for 184/198 DS controls.

Results: Deconvolution of blood cell proportions in the DS-ALL Discovery Study showed significantly higher B cell proportions in newborns with DS who later developed ALL (mean=0.0128, sd=0.0151) compared with DS controls (mean=0.00826, sd=0.0115) (P=6.4x10-4, coefficient=0.0052). A significantly higher B cell proportion at birth was also found in DS-ALL cases in the independent Replication Study (cases mean=0.048, sd=0.024; controls mean=0.039, sd=0.028; P=0.03, coefficient=0.015). In the Discovery Study, the B cell difference remained significant (P=5.8x10-3) with a similar effect size (coefficient=0.0045) after removal of GATA1 mutation-positive DS controls (n=30). We also investigated whether DS-ALL risk SNPs at ARID5B, IKZF1, GATA3, and CDKN2A may confound the association, but the increased B cell proportions in DS-ALL remained significant and effect estimates slightly increased in SNP genotype-adjusted models (coefficient range:0.0055-0.0059). In the EWAS of DS-ALL, 9 CpGs reached epigenome-wide significance (P<7.67x10-8), including 2 CpGs overlapping the promoter of the tumor suppressor gene TRIM13, frequently deleted in B-CLL, although none of these showed evidence of association (P<0.05) in the Replication Study. We identified 125 DMRs associated with DS-ALL in the Discovery Study. For 3 DMRs, overlapping genes HOPX, SMIM24, and PPP1R10, all implicated in normal and leukemic stem cell function, there were multiple significant CpGs in the Replication Study (P<0.05) all with effects in the same direction as the Discovery Study DMRs.

Conclusions: Increased B cell proportions in newborns with DS may be a risk factor for development of DS-ALL in childhood. This finding, based on DNA methylation data, requires confirmation using conventional cell count measures, and should be explored as a novel biomarker for ALL risk in the non-DS population. Single CpGs and DMRs associated with DS-ALL risk in our Discovery Study require further investigation, including in additional ALL case-control studies in DS and non-DS populations.

Disclosures: Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding.

*signifies non-member of ASH