Clinically Significant CUX1 Mutations Are Frequently Subclonal and Common in Myeloid Disorders With a High Number of Co-mutated Genes and Dysplastic Features

Abstract

Abstract Objectives CUX1 mutations have been reported in myeloid neoplasms. We aimed to characterize the mutational landscape, clonal architecture, and clinical characteristics of myeloid disorders with CUX1 variants. Methods We reviewed data from a targeted 62-gene panel with CUX1 variants. Variants were classified as of strong or potential clinical significance (tier I/tier II) or of unknown significance (VUS). Results CUX1 variants were identified in 169 cases. The 49 tier I/tier II variants were found in older patients (mean age, 71 vs 60 years old) and predominantly inactivating alterations, while the 120 VUS cases were missense mutations. Monosomy 7/deletion 7q was more common in tier I/tier II cases. Co-mutations were detected in 96% of tier I/tier II cases (average, 3.7/case) but in only 61% of VUS cases (average, 1.5/case). Tier I/tier II CUX1 variants tend to be subclonal to co-mutations (ASXL1, SF3B1, SRSF2, TET2). Among myeloid disorders, tier I/tier II cases were more frequently diagnosed with myelodysplastic syndromes and had a higher number of bone marrow dysplastic lineages. Conclusions CUX1 mutations are seen with adverse prognostic features and could be a late clonal evolutional event of myeloid disorders. The differences between CUX1 tier I/tier II and VUS underscore the importance of accurate variant classification in reporting of multigene panels.