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

The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) and is associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients have not been fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, seven CLL patients with several chromosomal gains were sequenced using 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 observed in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected; TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%), and BRAF (28.5%) were the most recurrently mutated genes. Of these mutations, 61.9% were detected in genes previously associated with a poor prognosis in CLL. Interestingly, five of the seven patients exhibited alterations in TP53 or ATM (deletion and/or mutation), genes involved in the 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 exhibit high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes.This work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias (PI15/01471, PI18/01500); by the Instituto de Salud Carlos III (ISCIII), European Regional Development Fund (ERDF) “Una manera de hacer Europa”; and by grants from Red Temática de Investigación Cooperativa en Cáncer (RTICC) and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) (RD12/0036/0069). MH-S is supported by FEHH-Janssen (“Sociedad Española de Hematología y Hemoterapia”). AER-V and JMH-S are supported by a research grant from FEHH (Fundación Española de Hematología y Hemoterapia). MQ-Á is supported by a grant from “Ayuda Predoctoral de la Junta de Castilla y León” (JCYL-EDU/529/2017)