Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk

• Published in: Nature communications Vol. 10; no. 1; pp. 5348 - 9
• Main Authors: Vijayakrishnan, Jayaram, Qian, Maoxiang, Studd, James B., Yang, Wenjian, Kinnersley, Ben, Law, Philip J., Broderick, Peter, Raetz, Elizabeth A., Allan, James, Pui, Ching-Hon, Vora, Ajay, Evans, William E., Moorman, Anthony, Yeoh, Allen, Yang, Wentao, Li, Chunliang, Bartram, Claus R., Mullighan, Charles G., Zimmerman, Martin, Hunger, Stephen P., Schrappe, Martin, Relling, Mary V., Stanulla, Martin, Loh, Mignon L., Houlston, Richard S., Yang, Jun J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.11.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/43; 631/208/205/2138; 631/67/1990/283/2125; 631/67/2332; 692/4028/67/1990/283/2125; Acute lymphoblastic leukemia; bcl-2 Homologous Antagonist-Killer Protein - genetics; Blood cancer; Cell cycle; Child; Chromatin; Chromosome 9; Core Binding Factor Alpha 2 Subunit - genetics; Deregulation; Epigenomics; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomic analysis; Humanities and Social Sciences; Humans; Leukemia; Loci; Lymphocytes B; multidisciplinary; Oncogene Proteins, Fusion - genetics; Polymorphism, Single Nucleotide; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Risk; Risk Factors; RNA-Binding Proteins - genetics; Runx1 protein; Science; Science (multidisciplinary); Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13069-6

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P  = 2.11 × 10 −8 ), for high-hyperdiploid ALL at 5q31.1 (rs886285, P  = 1.56 × 10 −8 ) and 6p21.31 (rs210143 in BAK1 , P   =  2.21 × 10 −8 ), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1 , P  = 1.82 × 10 −8 ). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL. B-cell acute lymphoblastic leukaemia (B-ALL) is a common childhood cancer. Here, the authors conducted a meta-analysis with four genome-wide association studies, totalling 5,321 cases and 16,666 controls of European descent, identifying B-ALL risk loci, whose integration with epigenomic profiling indicates cell-cycle and B-cell development deregulation as central mechanisms in B-ALL susceptibility, often in a subtype-specific fashion.