48 AJCP / Original article Am J Clin Pathol 2020;154:48-56 DOI: 10.1093/ajcp/aqaa016 © American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com Comparison of SF3B1/DNMT3A Comutations With DNMT3A or SF3B1 Mutation Alone in Myelodysplastic Syndrome and Clonal Cytopenia of Undetermined Significance Jinming Song, MD, PhD, Mohammad Hussaini, MD, Dahui Qin, MD, PhD, Xiaohui Zhang, MD, PhD, Haipeng Shao, MD, Ling Zhang, MD, David Gajzer, MD, Pukhraz Basra, MD , Lynn Moscinski, MD, and Hailing Zhang, MD From the Department of Hematopathology and Lab Medicine, H. Lee Mofftt Cancer Center and Research Institute, Tampa, FL. Key Words: DNMT3A; SF3B1; Mutation; MDS; CCUS; SF3B1/DNMT3A Am J Clin Pathol July 2020;154:48-56 DOI: 10.1093/AJCP/AQAA016 ABSTRACT Objectives: To compare the clinical signifcance of SF3B1/DNMT3A Comutations with SF3B1 or DNMT3A mutation alone in myelodysplastic syndrome (MDS) and clonal cytopenia of undetermined signifcance (CCUS). Methods: We identifed and compared 31 patients with only DNMT3A mutation, 48 patients with only SF3B1 mutation, and 16 patients with only SF3B1/DNMT3A comutations. Results: SF3B1/DNMT3A comutations were found to be more common in MDS, whereas DNMT3A mutation alone was more common in CCUS. The patients with SF3B1/DNMT3A comutations were less likely to have poor cytogenetics than patients with DNMT3A mutation alone. Patients with SF3B1/DNMT3A comutations showed signifcantly longer median survival time and better overall survival than patients with DNMT3A mutation alone. Conclusions: Patients with SF3B1/DNMT3A comutations appear to have better clinical outcomes than patients with isolated DNMT3A mutation. These fndings suggest that the favorable prognosis of SF3B1 mutation in is not abrogated by the concurrent presence of a DNMT3A mutation. Myelodysplastic syndrome (MDS) is a clonal mye- loid neoplasm that presents with cytopenia(s), morpho- logic dysplasia, and cytogenetic abnormalities and could progress into acute myeloid leukemia (AML) if untreated. Many patients with otherwise unexplained cytopenias will fail to meet the diagnostic criteria for MDS (>10% cells being dysplastic or with MDS-related cytogenetic abnor- malities) and are instead classified as having idiopathic cytopenias of undetermined significance (CUS). The clin- ical course of patients with idiopathic CUS appears to be highly variable; some go on to develop overt MDS, and some may follow a more indolent course. A population of the idiopathic CUS patients are found to have somatic mutations indicative of clonal hematopoiesis and are re- ferred to as clonal CUS (CCUS). 1 CCUS is a more fre- quent diagnosis than MDS in cytopenic patients. Some CCUS patients eventually progress into MDS. With the advent of next-generation sequencing (NGS) and eluci- dation of the clinical significance of somatic mutations in myeloid neoplasms, gene-mutation profiling has played an increasingly critical role in the diagnosis, prognostic stratification, and management of patients with MDS or CCUS. Different categories of somatic gene mutations have been identified in myeloid neoplasms. These include genes involved in DNA methylation (DNMT3A, TET2, IDH1/2), posttranslational chromatin modification (EZH2, ASXL1), RNA splicing (SF3B1, SRSF2, U2AF1, Downloaded from https://academic.oup.com/ajcp/article/154/1/48/5766453 by guest on 07 January 2023