Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome

Abstract

Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies have enabled the identification of a set of recurrently mutated genes central to the pathogenesis of MDS, which can be organized into a limited number of cellular processes, including RNA splicing, epigenetic and traditional transcriptional regulation, and signal transduction. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis to frank MDS, and, ultimately, to secondary AML. This detailed understanding of the molecular landscape of MDS, coupled with the emergence of cost-and time-effective methodologies for DNA sequencing has led to the introduction of genetic studies into the clinical realm. Here, we review recent advances in our genetic understanding of MDS, with a particular focus on the emerging role for mutational data in clinical management as a potential tool to assist in diagnosis, risk stratification, and therapeutic decision-making.J Clin Oncol 35:968-974.

Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS

“…MDS arises from abnormal hematopoietic stem cells, with detectable somatic mutations in virtually all patients [2,3], and recent studies also showed that germline mutations are found in a portion of MDS [4,5]. These results clearly demonstrate that the genomic status is highly influential on clinical features of MDS [3].…”

Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia

“…Classification of frequently mutated genes in MDS and CMML according to their functional category (modified from Kennedy & Ebert, ; Kennedy & Ebert, ).…”

“…Driver genes in MDS and CMML, which are common among the spectrum of myeloid malignancies, affect specific cellular processes and can be categorized according to their function (Greenberg et al, 2017;Kennedy & Ebert, 2017;McClure et al, 2018) (Fig 1).…”

“…Myeloid neoplasms arise through the serial acquisition of chromosomal alterations and somatic mutations that affect genes involved in several mechanisms. These mutations drive disease evolution from asymptomatic clonal haematopoiesis to overt disease and, eventually, progression to AML (Kennedy & Ebert, ). Recurrent mutations in more than 40 different genes have been identified in MDS and CMML and at least one mutation is detected at diagnosis in >80% of patients (Papaemmanuil et al , ; Haferlach et al , ; Elena et al , ).…”

“…Classification of frequently mutated genes in MDS and CMML according to their functional category (modified fromKennedy & Ebert, 2017;Kennedy & Ebert, 2017).Guideline ª 2019 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. British Journal of Haematology, 2020, 188, 605-622…”