Dataset Information

ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

ABSTRACT: Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ?1.33, Ptrend?0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction?0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction?0.12) among cases. These results indicate similar ALL risk across strata of known risk factors.

SUBMITTER: Linabery AM

PROVIDER: S-EPMC3731070 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Linabery Amy M AM Blommer Crystal N CN Spector Logan G LG Davies Stella M SM Robison Leslie L LL Ross Julie A JA

Leukemia research 20130518 8

Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios ≥1.33, Ptrend≤0.001). No heterogenei ...[more]

PMID: 23692655

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Project description:Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.

Project description:PurposeAsparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwinia chrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown.MethodsPatients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses.ResultsWe included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P = .03).ConclusionDiscontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.

Dataset Information

ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

Publications

ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.

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