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Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome
- Source :
- Blood. 134:1227-1237
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
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 = 5.32 × 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.
- Subjects :
- 0301 basic medicine
Immunology
Locus (genetics)
Single-nucleotide polymorphism
Genome-wide association study
GATA3 Transcription Factor
Biology
Polymorphism, Single Nucleotide
Biochemistry
Ikaros Transcription Factor
03 medical and health sciences
0302 clinical medicine
Gene Frequency
Genetic predisposition
Humans
Genetic Predisposition to Disease
Allele
Child
Allele frequency
Cyclin-Dependent Kinase Inhibitor p16
Genetics
Cell Biology
Hematology
CEBPE
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Penetrance
DNA-Binding Proteins
030104 developmental biology
030220 oncology & carcinogenesis
Down Syndrome
Genome-Wide Association Study
Transcription Factors
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....ac6411b8099270eef1ec45b424751b37