Abstract 222: Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome
Bibliographic record
Abstract
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 >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<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):Abstract nr 222.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".