In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 222-222
Abstract:
Purpose: Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) compared to children without DS. While genome-wide association studies (GWAS) have identified several susceptibility loci in childhood ALL, studies of ALL in children with DS are lacking. Therefore, we conducted the first GWAS of DS-ALL. Methods: We analyzed independent cohorts of: 1) 226 newly diagnosed DS-ALL cases from Children's Oncology Group (COG) ALL trials (2000-2013) and 436 DS controls from the National Down Syndrome Project (NDSP), 2) 124 additional COG ALL cases (2011-2015) and 336 additional NDSP DS controls, 3) 20 DS-ALL cases and 275 DS controls from Michigan neonatal bloodspots, and 4) 157 DS-ALL cases and 145 DS controls largely from neonatal bloodspots from California and Washington. Genotyping was performed with Affymetrix or Illumina single nucleotide polymorphism (SNP) arrays. STRUCTURE software was used to define European (372 cases, 1,056 controls), Hispanic (140 cases, 136 controls), and African (15 cases, 62 controls) genetic ancestry. After genome-wide imputation and quality control, ancestry- and cohort-specific associations were evaluated at & gt;6,000,000 autosomal SNPs with minor allele frequency ≥1%. Associations were meta-analyzed across cohort and ancestry groups, assuming additive allelic effects. Results: Genome-wide significant (p & lt;5x10-8) association signals were identified for known ALL susceptibility loci, including rs58923657 near IKZF1 (Odds Ratio [OR]=2.02, p=5.32x10-15), CDKN2A missense mutation rs3731249 (OR=3.63, p=3.91x10-10), rs3781093 near GATA3 (OR=1.73, p=2.89x10-8), and rs7090445 near ARID5B (OR=1.57, p=2.93x10-8). A novel potential risk locus was identified at chromosome 20q11.21 (rs78019519, OR=3.17, p=5.11x10-7) with consistent effects observed across each cohort and ancestry group. This SNP is in the promoter region of the oncogene TPX2 and is also associated with expression of HM13 in whole blood in the Genotype-Tissue Expression (GTEx) Portal. Conclusion: We confirmed that known ALL susceptibility loci in children without DS, including IKZF1, CDKN2A, GATA3, PIP4K2A and ARID5B, also confer risk of ALL in children with DS, with CDKN2A showing the largest effect size. We also identified a potentially novel locus associated with ALL susceptibility in DS at chromosome 20q11.21. Additional investigation of these loci is ongoing and may advance our understanding of DS-ALL etiology and biology. Citation Format: Austin L. Brown, Adam J. de Smith, Michael E. Scheurer, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Michael E. Zwick, Naomi Winick, Kelly Maloney, Anne L. Angiolillo, Reuven Schore, MIchael M. Burke, Wanda L. Salzer, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Elanor Feingold, Stephanie L. Sherman, Wenjian Yang, Meenakshi Devidas, Kyle Walsh, Andrew T. DeWan, Maria S. Pombo-de-Oliveira, Jeffrey W. Taub, Daniel Sinnett, Jasmine Healy, Jillian M. Birch, Lisa F. Barcellos, Helen Hansen, Ivan Smirnov, Charles G. Mullighan, Stephen P. Hunger, Ching-Hon Pui, Mignon Loh, Joe L. Wiemels, Xiaomei Ma, Catherine Metayer, Beth A. Mueller, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Ab stract nr 222.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2018-222
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2018
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
