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Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

ABSTRACT: The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr?=?0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr?=?0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr?=?0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

SUBMITTER: Sanchez-Maldonado JM

PROVIDER: S-EPMC7366925 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

Sánchez-Maldonado J M JM Campa D D Springer J J Badiola J J Niazi Y Y Moñiz-Díez A A Hernández-Mohedo F F González-Sierra P P Ter Horst R R Macauda A A Brezina S S Cunha C C Lackner M M López-Nevot M A MA Fianchi L L Pagano L L López-Fernández E E Potenza L L Luppi M M Moratalla L L Rodríguez-Sevilla J J JJ Fonseca J E JE Tormo M M Solano C C Clavero E E Romero A A Li Y Y Lass-Flörl C C Einsele H H Vazquez L L Loeffler J J Hemminki K K Carvalho A A Netea M G MG Gsur A A Dumontet C C Canzian F F Försti A A Jurado M M Sainz J J

Blood cancer journal 20200716 7

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T ...[more]

PMID: 32678078

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Project description:BackgroundWe sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment.MethodsFrom Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084.FindingsComplete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028).InterpretationOur findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML.FundingNational Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC).

Dataset Information

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

Publications

Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium.

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