👤 Manja Meggendorfer

Acute myeloid leukemia (AML) is a complex hematologic malignancy with multiple disease subgroups defined by somatic mutations and heterogeneous outcomes. Although genome-wide association studies (GWAS) have identified a small number of common genetic variants influencing AML risk, the heritable component of this disease outside of familial susceptibility remains largely undefined. Here, we perform a meta-analysis of 4 published GWAS plus 2 new GWAS, totaling 4710 AML cases and 12 938 controls. We identify a new genome-wide significant risk locus for pan-AML at 2p23.3 (rs4665765; P = 1.35 × 10-8; EFR3B, POMC, DNMT3A, and DNAJC27), which also significantly associates with patient survival (P = 6.09 × 10-3). Our analysis also identifies 3 new genome-wide significant risk loci for disease subgroups, including AML with deletions of chromosome 5 and/or 7 at 1q23.3 (rs12078864; P = 7.0 × 10-10; DUSP23) and cytogenetically complex AML at 2q33.3 (rs12988876; P = 3.28 × 10-8; PARD3B) and 2p21 (rs79918355; P = 1.60 × 10-9; EPCAM). We also investigated loci previously associated with the risk of clonal hematopoiesis (CH) or CH of indeterminate potential and identified several variants associated with the risk of AML. Our results further inform on AML etiology and demonstrate the existence of disease subgroup specific risk loci. Show less

Diverse haematological neoplasms are driven by tyrosine kinase (TK) fusion genes formed by recurrent or non-recurrent genomic rearrangements. The resulting chimeric proteins often present excellent targets for treatment with kinase inhibitors, and the fusion transcripts or genomic junctions can be used as specific targets for molecular monitoring. Whilst the TK genes involved are generally well characterised (e.g. ABL1, PDGFRA, FGFR1), the fusion partners are very diverse, presenting a challenge for detection and characterisation of these structural variants (SV) using current diagnostic methods. We assessed the ability of targeted nanopore sequencing using adaptive sampling to detect fusion genes in myeloid neoplasms. We sequenced genomic DNA from patients (n = 20) with a known or suspected TK gene fusion and identified rearrangements in 18 cases, including all cases with a known TK fusion, typical and atypical BCR::ABL1 rearrangements, an 843Kb deletion causing a FIP1L1::PDGFRA fusion, novel AGAP2::PDGFRB and NFIA::PDGFRB fusions, and a complex CCDC88C::PDGFRB rearrangement with multiple translocation events. The approach was fast (<72 h/sample from DNA to result), flexible with minimal hands-on laboratory time, and provided accurate, patient-specific characterisation of genomic breakpoints. Show less

Mixed-lineage leukemia (MLL) gene rearrangements are among the most frequent chromosomal abnormalities in acute myeloid leukemia (AML). MLL fusion patterns are associated with the patient's prognosis; however, their relationship with driver mutations is unclear. We conducted sequence analyses of 338 genes in pediatric patients with MLL-rearranged (MLL-r) AML (n = 56; JPLSG AML-05 study) alongside data from the TARGET study's pediatric cohorts with MLL-r AML (n = 104), non-MLL-r AML (n = 581), and adult MLL-r AML (n = 81). KRAS mutations were most frequent in pediatric patients with high-risk MLL fusions (MLL-MLLLT10, MLL-MLLT4, and MLL-MLLT1). Pediatric patients with MLL-r AML (n = 160) and a KRAS mutation (KRAS-MT) had a significantly worse prognosis than those without a KRAS mutation (KRAS-WT) (5-year event-free survival [EFS]: 51.8% vs 18.3%, P < .0001; 5-year overall survival [OS]: 67.3% vs 44.3%, P = .003). The adverse prognostic impact of KRAS mutations was confirmed in adult MLL-r AML. KRAS mutations were associated with adverse prognoses in pediatric patients with both high-risk (MLLT10+MLLT4+MLLT1; n = 60) and intermediate-to-low-risk (MLLT3+ELL+others; n = 100) MLL fusions. The prognosis did not differ significantly between patients with non-MLL-r AML with KRAS-WT or KRAS-MT. Multivariate analysis showed the presence of a KRAS mutation to be an independent prognostic factor for EFS (hazard ratio [HR], 2.21; 95% confidence interval [CI], 1.35-3.59; P = .002) and OS (HR, 1.85; 95% CI, 1.01-3.31; P = .045) in MLL-r AML. The mutation is a distinct adverse prognostic factor in MLL-r AML, regardless of risk subgroup, and is potentially useful for accurate treatment stratification. This trial was registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry (UMIN-CTR; http://www.umin.ac.jp/ctr/index.htm) as #UMIN000000511. Show less