Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome

Austin L. Brown, Adam J. De Smith, Vincent U. Gant, Wenjian Yang, Michael E. Scheurer, Kyle M. Walsh, Jonathan M. Chernus, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Naomi Winick, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Eleanor Feingold, Meenakshi DevidasLisa F. Barcellos, Helen M. Hansen, Libby Morimoto, Alice Y. Kang, Ivan Smirnov, Jasmine Healy, Caroline Laverdie`re, Daniel Sinnett, Jeffrey W. Taub, Jillian M. Birch, Pamela Thompson, Logan G. Spector, Maria S. Pombo-De-Oliveira, Andrew T. DeWan, Charles G. Mullighan, Stephen P. Hunger, Ching Hon Pui, Mignon L. Loh, Michael E. Zwick, Catherine Metayer, Xiaomei Ma, Beth A. Mueller, Stephanie L. Sherman, Joseph L. Wiemels, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ~50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta 5 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta 5 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta 58.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta52.8931028).We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta 54.1 × 10-4). This association wasmaintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Original languageEnglish (US)
Pages (from-to)1227-1237
Number of pages11
JournalBlood
Volume134
Issue number15
DOIs
StatePublished - Oct 10 2019

    Fingerprint

PubMed: MeSH publication types

  • Journal Article
  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

Cite this

Brown, A. L., De Smith, A. J., Gant, V. U., Yang, W., Scheurer, M. E., Walsh, K. M., Chernus, J. M., Kallsen, N. A., Peyton, S. A., Davies, G. E., Ehli, E. A., Winick, N., Heerema, N. A., Carroll, A. J., Borowitz, M. J., Wood, B. L., Carroll, W. L., Raetz, E. A., Feingold, E., ... Rabin, K. R. (2019). Inherited genetic susceptibility to acute lymphoblastic leukemia in down syndrome. Blood, 134(15), 1227-1237. https://doi.org/10.1182/blood.2018890764