Clinically Significant CUX1 Mutations Are Frequently Subclonal and Common in Myeloid Disorders With a High Number of Co-mutated Genes and Dysplastic Features. Issue 4 (18th October 2021)

• Record Type: Journal Article
• Authors: Dermawan, Josephine K; Wensel, Christine; Visconte, Valeria; Maciejewski, Jaroslaw P; Cook, James R; Bosler, David S
• Is Part Of: American journal of clinical pathology. Volume 157:Issue 4(2022)
• Page Start: 586
• Page End: 594
• Publication Date: 2021-10-18
• Subjects: CUX1 -- Co-mutations -- Clonality -- Myeloid neoplasms -- Variant classification; Diagnosis, Laboratory -- Periodicals; Pathology -- Periodicals; 616.07
• DOI: 10.1093/ajcp/aqab157
• Languages: English
• ISSNs: 0002-9173

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.