Influence of Nucleophosmin () Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.

PURPOSE

Several genomic subsets of mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.

MATERIALS AND METHODS

Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known genotype and available outcome were selected for this study. Diverse variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the variants was studied.

RESULTS

Evaluation of clinical outcome on the basis of genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D 86% for type non-D, = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed mRNA and protein, mediating peculiar mitochondrial gene expression.

CONCLUSION

The evaluation of specific genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.