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

<bold>Objectives: </bold>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.<bold>Methods: </bold>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).<bold>Results: </bold>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.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]