Balanced and unbalanced translocations in a multicentric series of 2843 patients with chronic lymphocytic leukemia

Abstract

Chromosomal translocations in chronic lymphocytic leukemia (CLL) are very rare, and therefore systematic analysis of large series of cases is needed to allow the identification of recurrent rearrangements, breakpoints involved, and target genes.The aims of the present study were to identify new translocations and their clinical impact and to establish their frequency in a large cohort of 2843 CLL patients. By conventional cytogenetics 250 translocations were identified in 215 (7.5%) patients, 186 (74%) were apparently balanced and 64 (26%) were unbalanced. All chromosomes were involved in translocations, except Y chromosome. The chromosomes more frequently translocated were in decreasing frequency chromosomes 14, 18, 13, 17, 1, 6, 2, 3, 8, and 11. Translocations were found in the karyotypes either as the unique chromosomal abnormality (27%), associated with another alteration (24%), or as a part of a complex karyotype (CK, 48%). A large proportion of rearranged breakpoints involved genes related to CLL such as IGH (14q32), RB1, MIR15A, MIR16-1 (13q14), BCL2 (18q21), IGL (22q11.2), TP53 (17p13), IRF4 (6p25-p23), ATM (11q22), and CDK6 (7q21). Overall, 76 novel CLL translocations were identified, including a recurrent t(8;11) (p21;q21-23). Whole-genome sequencing and/or copy-number microarray data of 24 cases with translocations confirmed all rearrangements, enabled refinement of 3 karyotypes and all breakpoints at gene level. The projected survival and time to first treatment significantly decreased linearly with the number of translocations. In summary, this study allowed to establish the frequency of translocations (7.5%) and to identify new translocations in a cohort of 2843 CLL patients.

Balanced chromosomal rearrangements offer insights into coding and noncoding genomic features associated with developmental disorders

“…These included two established DD genes ( AUTS2, MBD5 ) 45,46 and one candidate DD gene, CDK6 , which was disrupted in three cases that presented with developmental delay ( n = 3), speech delay ( n = 2), microcephaly ( n = 2), and cardiac defects ( n = 1). CDK6 is highly constrained against damaging point mutations, 47 is ubiquitously expressed across tissues, 48,49 and encodes a cyclin-dependent kinase with major roles in skin, blood, and breast cancers. 50 CDK6 has also been associated with a recessive form of primary microcephaly, 51 but has not been previously associated with dominant germline disease.…”

TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype

“…This phenomenon was first identified in prostate cancer, with a prevalence of ~90%, and is also present in other solid tumors [ 42 , 43 ]. However, despite being described in some hematological neoplasms, such as multiple myeloma, mantle cell lymphoma or in previous reports on CLL [ 24 , 44 , 45 , 46 ], clinical and biological differences between both chromoplexy and cth and their impact on CLL have not been further explored. In this study, no differences in clinical characteristics could be identified among patients showing the aforementioned rearrangement patterns, although it should be noted that the cohort was too small to draw any conclusion.…”

Detection of a Cryptic 25 bp Deletion and a 269 Kb Microduplication by Nanopore Sequencing in a Seemingly Balanced Translocation Involving the LMLN and LOC105378102 Genes

“…Hundreds of patients are diagnosed as apparently balanced translocation with chromosomal karyotype at our center every year. Approximately half of the seemingly balanced translocations were in fact unbalanced ( De Gregori et al, 2007 ; Costa et al, 2022 ). The number of patients facing reproductive difficulty was large.…”