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Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Publication ,  Journal Article
Brown, AL; de Smith, AJ; Gant, VU; Yang, W; Scheurer, ME; Walsh, KM; Chernus, JM; Kallsen, NA; Peyton, SA; Davies, GE; Ehli, EA; Winick, N ...
Published in: Blood
October 10, 2019

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 = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). 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 = 4.1 × 10-4). This association was maintained 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.

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 10, 2019

Volume

134

Issue

15

Start / End Page

1227 / 1237

Location

United States

Related Subject Headings

  • Transcription Factors
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Immunology
  • Ikaros Transcription Factor
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Frequency
  • GATA3 Transcription Factor
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Brown, A. L., de Smith, A. J., Gant, V. U., Yang, W., Scheurer, M. E., Walsh, K. M., … 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

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

October 10, 2019

Volume

134

Issue

15

Start / End Page

1227 / 1237

Location

United States

Related Subject Headings

  • Transcription Factors
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Polymorphism, Single Nucleotide
  • Immunology
  • Ikaros Transcription Factor
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Gene Frequency
  • GATA3 Transcription Factor