{Reference Type}: Journal Article
{Title}: Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition.
{Author}: Giudice V;Serio B;Errichiello S;Ferrara I;Galdiero A;Bertolini A;Visconti R;De Novellis D;Guariglia R;Luponio S;Morini D;Della Corte AM;Sessa AM;Verdesca F;Langella M;Izzo B;Selleri C;
{Journal}: Eur J Haematol
{Volume}: 111
{Issue}: 5
{Year}: 2023 Nov
{Factor}: 3.674
{DOI}: 10.1111/ejh.14069
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.