The incidence and mortality rates of B-cell acute lymphoblastic leukemia (B-ALL) differ by age and sex. To determine if inherited genetic susceptibility contributes to these differences we performed 2 genome-wide association studies (GWAS) by age, sex, and subtype and subsequent meta-analyses. The GWAS included 446 B-ALL cases, and 3027 healthy unrelated blood and marrow transplant (BMT) donors as controls from the Determining the Influence of Susceptibility Conveying Variants Related to One-Year Mortality after BMT (DISCOVeRY-BMT) study. We identified 1 novel variant, rs189434316, significantly associated with odds of normal cytogenetic B-ALL (odds ratio from meta-analysis [ORmeta] 5 3.7; 95% confidence interval [CI], 2.5, 6.2; P value from meta-analysis [Pmeta] 5 6.0 3 1029). The previously reported pediatric B-ALL GWAS variant, rs11980379 (IKZF1), replicated in B-ALL pediatric patients (ORmeta 5 2.3; 95% CI, 1.5, 3.7; Pmeta 5 1.0 3 1029), with evidence of heterogeneity (P 5 .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those .15 years (OR 5 1.7; 95% CI, 1.4, 2.2, PMales 5 6.38 3 1026/OR 5 1.1; 95% CI, 0.8, 1.5; PFemales 5 .6) but not #15 years (OR 5 2.3; 95% CI, 1.4, 3.8; PMales 5 .0007/OR 5 1.9; 95% CI, 1.2, 3.2; PFemales 5 .007). The latter association replicated in independent pediatric B-ALL cohorts. A previously identified adolescent and young-adult onset ALL-associated variant in GATA3 is associated with B-ALL risk in those .40 years. Our findings provide more evidence of the influence of genetics on B-ALL age of onset and we have shown the first evidence that IKZF1 associations with B-ALL may be sex and age specific.
Bibliographical noteFunding Information:
The German GWAS was supported by the German Ministry of Education and Research (Bundesministeriums f?r Bildung und Forschung) through the National Genome Research Network, the popgen biobank, the Federal Radiation Protection Agency (project no. 3609S30013), the Deutsche Krebshilfe, and the Madeleine Schickedanz Kinderkrebs-Stiftung; received infrastructure support through the Deutsche Forschungsgemeinschaft excellence cluster ?Inflammation at Interfaces?; and was conducted within the frame of the International BFM Study Group.
Replication data sets were supported by grants from the National Institutes of Health (Eunice Kennedy Shriver National Institute of Child Health and Human Development HD0433871; National Cancer Institute CA129045 and CA40046 [K.O.]; National Institute of Mental Health R01 MH101820; National Cancer Institute U01CA176063 and National Institute of General Medical Sciences U01GM92666); the St. Baldrick’s Foundation (K.O.); the American Cancer Society, Illinois Division (K.O.); and the Cancer Research Foundation (K.O.).
The Center for International Blood and Marrow Transplant Research was supported by US Public Health Service grant/ cooperative agreement 5U24-CA076518 from the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; grant/ cooperative agreement 5U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute; contract HHSH250201200016C with the Health Resources and Services Administration/US Department of Health and Human Services; grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research; and grants from Alexion; Amgen, Inc*; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Be the Match Foundation; Bluebird Bio, Inc*; Bristol-Myers Squibb Oncology*; Celgene Corporation*; Cellular Dynamics International, Inc; Chimerix, Inc*; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd; Genentech, Inc; Genzyme Corporation; Gilead Sciences, Inc*; Health Research, Inc; Roswell Park Cancer Institute; HistoGenetics, Inc; Incyte Corporation; Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals, Inc*; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; Merck & Co, Inc*; Mesoblast; MesoScale Diagnostics, Inc; Miltenyi Biotec, Inc*; National Marrow Donor Program; Neovii Biotech NA, Inc; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc; Otsuka America Pharmaceutical, Inc; Otsuka Pharmaceutical Co, Ltd Japan; Patient-Centered Outcomes Research Institute; Perkin Elmer, Inc; Pfizer, Inc; Sanofi US*; Seattle Genetics*; Spectrum Pharmaceuticals, Inc*; St. Baldrick’s Foundation; Sunesis Pharmaceuticals, Inc*; Swedish Orphan Biovitrum, Inc; Takeda Oncology; Telomere Diagnostics, Inc; University of Minnesota; and Wellpoint, Inc* (*corporate members).
The Children’s Oncology Group GWAS was also supported by grants from the National Institutes of Health, National Cancer Institute (the Chair’s grant U10 CA98543 and Human Specimen Banking grant U24 CA114766).
Conflict-of-interest disclosure: T.H. owns stock in Novartis Pharmaceuticals Corporation. D.J.W. provided consulting services to, and served on advisory boards for, Kadmon and Alexion, and received research funding from Alexion. S.S. received compensation for travel, accommodations, and expenses from Astel-las Pharma. M.C.P. received honoraria, as well as compensation for travel, accommodations, and expenses, from Baxalta and Atara Biotherapeutics. P.L.M. received honoraria from Celgene, Bristol-Myers Squibb, Janssen Pharmaceutical, Sanofi, and Karyopharm Therapeutics Inc; research funding from Celgene; and compensation for travel, accommodations, and expenses from Celgene and Sanofi. The remaining authors declare no competing financial interests.
The German GWAS was supported by the German Ministry of Education and Research (Bundesministeriums für Bildung und Forschung) through the National Genome Research Network, the popgen biobank, the Federal Radiation Protection Agency (project no. 3609S30013), the Deutsche Krebshilfe, and the Madeleine Schickedanz Kinderkrebs-Stiftung; received infrastructure support through the Deutsche Forschungsgemeinschaft excellence cluster “Inflammation at Interfaces”; and was conducted within the frame of the International BFM Study Group.
This work was supported by the National Institutes of Health: National Cancer Institute grant R03 CA188733 (L.E.S.-C. and T.H.), National Heart, Lung, and Blood Institute grant R01 HL102278 (which funded DISCOVeRY-BMT) (L.E.S.-C. and T.H.), and National Cancer Institute grant P30 CA016056 (which partially supported the Roswell Park Cancer Institute Biostatistics & Bioinformatics Core).
© 2017 by The American Society of Hematology.