%0 Journal Article
%T Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition.
%A Giudice V
%A Serio B
%A Errichiello S
%A Ferrara I
%A Galdiero A
%A Bertolini A
%A Visconti R
%A De Novellis D
%A Guariglia R
%A Luponio S
%A Morini D
%A Della Corte AM
%A Sessa AM
%A Verdesca F
%A Langella M
%A Izzo B
%A Selleri C
%J Eur J Haematol
%V 111
%N 5
%D 2023 Nov
%M 37501402
%F 3.674
%R 10.1111/ejh.14069
%X BACKGROUND: Splicing 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.
METHODS: A 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.
RESULTS: We 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.
CONCLUSIONS: In 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.