Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

Abstract

BackgroundSplicing modifications, genomic instability, and hypomethylation are central mechanisms promoting myelodysplasia and acute myeloid leukemia (AML). In this real‐life retrospective study, to elucidate pathophysiology of clonal hemopoiesis in hematological malignancies, we investigated clinical significance of mutations in leukemia‐related genes of known pathogenetic significance and of variants of uncertain clinical significance (VUS) in a cohort of patients with MDS and AML.MethodsA total of 59 consecutive subjects diagnosed with MDS, 48 with AML, and 17 with clonal cytopenia with unknown significance were screened for somatic mutations in AML‐related genes by next‐generation sequencing.ResultsWe showed that TET2, SETBP1, ASXL1, EZH2, RUNX1, SRSF2, DNMT3A, and IDH1/2 were commonly mutated. MDS patients also showed a high genetic complexity, especially for SETBP1. Moreover, the presence of SETBP1 wild‐type or two or more simultaneous VUS variants identified a subgroup of AML and MDS patients with better outcome, while the presence of single SETBP1 VUS variant was related to a worse prognosis, regardless TET2 mutational status.ConclusionsIn conclusions, we linked both pathogenic and VUS variants in AML‐related genes to clonal hematopoiesis; therefore, we proposed to consider those variants as prognostic markers in leukemia and myelodysplasia. However, further studies in larger prospective cohorts are required to validate our results.

Non-invasive prenatal test identifies circulating cell-free DNA chromosomal abnormalities derived from clonal hematopoiesis in aggressive hematological malignancies

“…Circulating cell-free DNA (cfDNA) is shed by apoptotic or necrotic cells, such as highly proliferating cancer cells, and released into the bloodstream, thus being extremely representative of tumor tissue genomic heterogeneity, such as during Hodgkin (HL) and non-Hodgkin B-cell lymphomas [ 6 – 8 ]. Moreover, somatic variants detected in cfDNA can derive from clonal hematopoiesis, a branched evolution hematopoietic model in which multiple co-existing clones diverge and evolve in parallel with the acquisition of additional somatic mutations that might lead to tumor development [ 9 ]. Recurrent somatic mutations are found in most hematological malignancies, such as myelodysplasia, with disease-specific mutated gene patterns, have diagnostic and/or prognostic significance, and can be used as a pharmacological targets; however, clonal hematopoiesis is common in older general population with unknown clinical significance [ 10 ].…”