Chromothripsis in Chronic Lymphocytic Leukemia: A Driving Force of Genome Instability

Abstract

Chromothripsis represents a mechanism of massive chromosome shattering and reassembly leading to the formation of derivative chromosomes with abnormal functions and expression. It has been observed in many cancer types, importantly, including chronic lymphocytic leukemia (CLL). Due to the associated chromosomal rearrangements, it has a significant impact on the pathophysiology of the disease. Recent studies have suggested that chromothripsis may be more common than initially inferred, especially in CLL cases with adverse clinical outcome. Here, we review the main features of chromothripsis, the challenges of its assessment, and the potential benefit of its detection. We summarize recent findings of chromothripsis occurrence across hematological malignancies and address its causes and consequences in the context of CLL clinical features, as well as chromothripsis-related molecular abnormalities described in published CLL studies. Furthermore, we discuss the use of the current knowledge about genome functions associated with chromothripsis in the optimization of treatment strategies in CLL.

A Peculiar CLL Case with Complex Chromosome 6 Rearrangements and Refinement of All Breakpoints at the Gene Level by Genomic Array: A Case Report

“…Although we recognize that WGS is the only technique capable to define chromoanagenesis, such event can be inferred also by peculiar genome array profiles. Despite rarely being investigated in clinical trials, there is suggestive evidence that chromoanagenesis may confer worse survival in CLL [ 55 ]. In our case, the elevated number (eighteen) of breakpoints in the long arm of chromosome 6 fulfills the criteria for a bona fide chromotripsis-like event.…”

Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia

“…Cth has also been detected in various types of hematological neoplasms, including multiple myeloma, chronic lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, and lymphoma, with frequencies ranging between 1% and 89%. However, in the majority of blood malignancies, it has been noted in less than 10% of patients, depending on the cth detection method (12). Cth has also been observed in very de ned and rare subtypes of ALL, including ETP-ALL, BCP-ALL with internal ampli cation of chromosome 21 (iAMP21), and T-ALL, which develop in the constitutional background of ataxia telangiectasia (8, 13,14).…”