Ring Chromosomes in Hematological Malignancies Are Associated with TP53 Gene Mutations and Characteristic Copy Number Variants

SIMPLE SUMMARY: Ring chromosomes (RCs) are formed when chromosome ends fuse to form a circular structure. RCs are seen in <10% of patients with blood cancers (i.e., leukemias, lymphomas, and myelomas), and are associated with poor disease outcomes. We sought to evaluate how frequently RCs arise in patients diagnosed with these cancers and determine if there are any associated genetic variants, regions, or chromosomal abnormalities. Most patients with RCs have mutations in the TP53 gene and gross chromosomal rearrangements, particularly among chromosomes 5, 7, 11, and 17. Most of these patients also possess marker chromosomes with genetic material of unknown origin. The majority of RCs that resemble identifiable chromosomes, as well as chromosomes lacking gross rearrangements, were seen in patients without TP53 mutations. Our data suggest that mechanisms underlying RC generation may arise differently in patient groups with the presence or absence of functional TP53, a potentially important distinction for clinical decision making. ABSTRACT: Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs—90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.