DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia patients and chromosomal gains.

The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) being associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients are not fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, 7 CLL patients with several chromosomal gains were sequenced by a next generation sequencing (NGS)-targeted approach. The mutational status of 54 genes was evaluated using a custom-designed gene panel including recurrent mutated genes in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected, being TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%) and BRAF (28.5%) the most recurrently mutated genes. 61.9% of the mutations were detected in genes previously associated with poor prognosis in CLL. Interestingly, five out of seven patients showed alterations in TP53 or ATM (deletion and/or mutation), genes involved in DNA damage response (DDR), which could be related to a high genetic instability in this subgroup of patients. In conclusion, CLL patients with several chromosomal gains show a high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes.