Chromoanagenesis in Myelodysplastic Syndromes Is Associated With Highly Complex Karyotype, TP53 Disruption, and Dismal Prognosis.

Abstract

Chromoanagenesis (CAG) is a catastrophic genomic event characterized by extensive chromosomal rearrangements and copy number alterations. It has been associated with complex karyotypes and poor outcomes in acute myeloid leukemia. However, its prevalence and associated clinicopathologic and cytogenomic features in myelodysplastic syndromes (MDSs) remain incompletely defined. In this study, we performed optical genome mapping in 332 patients with MDS, 205 newly diagnosed (ND), and 127 relapsed/refractory (R/R) cases. CAG was identified in 15.9% of cases overall and in 17.6% of ND MDS. Among ND patients, 97% of CAG cases harbored highly complex karyotypes versus 9% of non-CAG cases (P < .01). TP53 alterations were present in 97% of CAG cases, predominantly multihit events, whereas mutations in canonical MDS driver genes were uncommon in CAG cases. Recurrent oncogenic amplifications, including 11q23/KMT2A and 6p21/PIM1 and HMGA1, were enriched in CAG cases. Clinically, 80.6% of CAG cases were classified as very high risk by Molecular International Prognostic Scoring System. Median overall survival of patients with ND CAG was 9.9 months versus not reached in non-CAG cases (P < .01), and survival of CAG cases remained inferior compared with patients with non-CAG having very high Molecular International Prognostic Scoring System risk (20.4 months) or multihit TP53 alterations (18.3 months). We conclude that CAG defines a biologically distinct, ultra-high-risk subset of MDS characterized by TP53 disruption, extreme genomic complexity, and dismal prognosis. Optical genome mapping enables efficient CAG detection and may refine current risk stratification.