Germline SNPs previously implicated as prognostic biomarkers do not associate with outcomes in intensively treated AML.

Although acute myeloid leukemia (AML) is caused by somatically acquired gene mutations, germline variants can also modulate disease characteristics such as sensitivity to treatment and are therefore associated with patient outcomes. Several single-nucleotide polymorphisms (SNPs) have been iden-tified in the past decade to be significantly associated with patient characteristics such as survival, therapy response, and other outcome variables in AML.(1-3) Furthermore, susceptibility loci are increasingly recognized as being associated with the risk to develop leukemia.(4-6) Although these led to some intriguing hypotheses, SNPs are currently not included in routine risk assessment.7 Guidelines provided by the European LeukaemiaNet (ELN) in 2017 and 2022 improved risk stratification of patients with AML; however, recent publications suggest that further improvement beyond ELN2017 is possible.(7,8) In this context, SNPs present attractive candidates because they can easily be implemented in current routine panel sequencing analysis. Multiple studies have reported associations between germline polymorphisms and disease character-istics in AML.(1,9-14) For example, SNP rs12036333 (G>A, LINC01139;CHRM3) has been associated with inferior overall survival (OS) and relapse-free survival (RFS).(9,10) Furthermore, many studies reported associations of SNPs with clinical characteristics (supplemental Table 1). However, these associations are often derived from small cohorts and have not been systematically validated so far. In addition, to our knowledge, there has not yet been a comprehensive analysis of the prognostic/clinical relevance of common SNPs in genes linked to AML pathogenesis. The aim of our study, therefore, was to validate previously identified SNPs that were associated with AML outcomes in prior publications in a large and uniformly treated patient cohort. As a secondary goal, we investigated the potential prog-nostic role of SNPs in genes commonly affected by somatic mutations in AML, which are included in most routinely used diagnostic panels, because such polymorphisms might allow any easily imple-mentable refinement of risk classifications. Local ethic committees of participating institutions approved all protocols, and patients were treated according to the Declaration of Helsinki.