Obesity As a Risk Factor for Acute Promyelocytic Leukemia. Results from Population and Case-Control Studies Across Western Countries and Correlation with Gene Expression in the TCGA

Background. Much uncertainty remains over the aetiology of Acute Myeloid Leukemia (AML) and of its biological subtypes, of which Acute Promyelocytic Leukemia (APL) is the best defined. In recent years, an elevated Body Mass Index (BMI) has been identified as a risk factor for several diseases. Whether BMI influences risk of developing AML and APL is not well understood.

Methods. We have collated information from population-based and case-control studies conducted in four different countries. In the population-based study, we obtained data from the Clinical Practice Research Datalink, that includes primary care data of 5.2 million UK citizens. We identified APL and other leukemia cases using ICD identifiers ("APL" (n=24), "non APL-AML" (n=972), lymphoid leukemias ("LL", n=2724) and "other" (n=1850). We fitted linear models to investigate the association between BMI and any of the above leukemic classes. In the case-control studies, we analysed data from patients included in the PETHEMA (Spain, n=414) and GIMEMA (Italy, n=134) databases and patients from the USA-based AML genome sequencing study (the AML TCGA cohort with 22 additional cases characterized at Washington University-St Louis, n=42) ("case" cohorts). We then created age-, gender, ethnicity- and year of diagnosis-matched control cohorts from national BMI surveys and tested deviation of observed cases from expected controls.

Lastly, we applied Quantitative Set Analysis for Gene Expression (quSAGE) analysis to investigate APL- or BMI-specific gene expression signatures from TCGA data

Findings. In the UK population study, the Hazard Ratio per each 5 kg/m² increase was 1.44 for APL (95% CI 1.0-2.08), 1.17 for non APL-AML (95% CI 1.10-1.26), 1.04 for LL (95% CI 1.0-1.09) and 1.10 for other leukemias (95% CI 1.04-1.15). In the case-control studies, BMI distribution in cases was significantly higher than expected from controls for all three cohorts: (Italy p<0.001, Spain p=0.011, USA p<0.001). quSAGE transcriptional analysis revealed significant enrichment of several pathways in APL vs other AMLs, in particular arachidonic and linoleic acid metabolism and upregulation of Insulin and IGF1 receptors.

Interpretation. A higher BMI was associated with increased risk of leukemia, particularly APL; increased risk of APL was confirmed in all populations examined, irrespective of gender or ethnicity. Elevated BMI should be considered a risk factor for APL development. APL is associated with a characteristic metabolic transcriptional signature that might be responsible for some of its clinical features