title: MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.
abstract: Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood.
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Brian
authors.initials: B
authors.lastname: Kwok
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Hall
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA; and.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Prashanti
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Keming
authors.initials: K
authors.lastname: Lin
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Rachel
authors.initials: R
authors.lastname: Flamholz
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Bashar
authors.initials: B
authors.lastname: Dabbas
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Aine
authors.initials: A
authors.lastname: Yung
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Jenan
authors.initials: J
authors.lastname: Al-Hafidh
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Emily
authors.initials: E
authors.lastname: Balmert
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Christine
authors.initials: C
authors.lastname: Vaupel
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Carlos
authors.initials: C
authors.lastname: El Hader
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McGinniss
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Shareef A
authors.initials: SA
authors.lastname: Nahas
authors.affiliation: Genoptix Medical Laboratory, Carlsbad, CA;
authors.forename: Julie
authors.initials: J
authors.lastname: Kines
authors.affiliation: Division of Hematology-Oncology, Moores Cancer Center at the University of California at San Diego, La Jolla, CA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
mesh_terms: D000367:Age Factors; D000483:Alleles; D002869:Chromosome Aberrations; D005260:Female; D005787:Gene Frequency; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D012189:Retrospective Studies