title: Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression.
abstract: The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphologic assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease; however, this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterizing 69 patients who, following a nondiagnostic marrow, developed progressive dysplasia or acute myeloid leukemia. Targeted sequencing and array-based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of prediagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population, the mutations detected had significantly greater median variant allele fraction (40% vs 9% to 10%), and occurred more commonly with additional mutations (≥2 mutations, 64% vs 8%). Furthermore, mutational analysis identified a high-risk group of patients with a shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor-risk patients.
authors.affiliation: Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom;
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cargo
authors.affiliation: Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom;
authors.forename: Nicola
authors.initials: N
authors.lastname: Rowbotham
authors.affiliation: Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom;
authors.forename: Paul A
authors.initials: PA
authors.lastname: Evans
authors.affiliation: Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom;
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Barrans
authors.affiliation: St James's Institute of Oncology, Leeds Teaching Hospitals, Leeds, United Kingdom; and.
authors.forename: David T
authors.initials: DT
authors.lastname: Bowen
authors.affiliation: Epidemiology and Cancer Statistics Group, University of York, York, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Crouch
authors.affiliation: Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom;
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Jack
mesh_terms: D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality*; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate