Genetic association with B-cell acute lymphoblastic leukemia in allogeneic transplant patients differs by age and sex

• Published in: Blood advances Vol. 1; no. 20; pp. 1717 - 1728
• Main Authors: Clay-Gilmour, Alyssa I., Hahn, Theresa, Preus, Leah M., Onel, Kenan, Skol, Andrew, Hungate, Eric, Zhu, Qianqian, Haiman, Christopher A., Stram, Daniel O., Pooler, Loreall, Sheng, Xin, Yan, Li, Liu, Qian, Hu, Qiang, Liu, Song, Battaglia, Sebastiano, Zhu, Xiaochun, Block, AnneMarie W., Sait, Sheila N.J., Karaesmen, Ezgi, Rizvi, Abbas, Weisdorf, Daniel J., Ambrosone, Christine B., Tritchler, David, Ellinghaus, Eva, Ellinghaus, David, Stanulla, Martin, Clavel, Jacqueline, Orsi, Laurent, Spellman, Stephen, Pasquini, Marcelo C., McCarthy, Philip L., Sucheston-Campbell, Lara E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.09.2017; The American Society of Hematology; American Society of Hematology; Elsevier
• Subjects: Life Sciences; Lymphoid Neoplasia
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017006023

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] = 3.7; 95% confidence interval [CI], 2.5, 6.2; P value from meta-analysis [Pmeta] = 6.0 × 10−9). The previously reported pediatric B-ALL GWAS variant, rs11980379 (IKZF1), replicated in B-ALL pediatric patients (ORmeta = 2.3; 95% CI, 1.5, 3.7; Pmeta = 1.0 × 10−9), with evidence of heterogeneity (P = .02) between males and females. Sex differences in single-nucleotide polymorphism effect were seen in those >15 years (OR = 1.7; 95% CI, 1.4, 2.2, PMales = 6.38 × 10−6/OR = 1.1; 95% CI, 0.8, 1.5; PFemales = .6) but not ≤15 years (OR = 2.3; 95% CI, 1.4, 3.8; PMales = .0007/OR = 1.9; 95% CI, 1.2, 3.2; PFemales = .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. [Display omitted] •IKZF1 associations with high-risk B-ALL may differ by age and sex.•A novel variant on chromosome 14, rs189434316, is associated with over a 3.5-fold risk of normal cytogenetic B-ALL.