A study indicated evidence of ongoing class switch recombination (CSR) and somatic hypermutation (SHM) in a significant subset of chronic lymphocytic leukemia (CLL) samples, which may show the functionality of DNA damage repair pathways. The study was presented as part of the 2020 ASCO Virtual Scientific Program.
Researchers obtained peripheral blood RNA from 63 individuals with CLL and four with splenic marginal zone lymphoma (SMZ). They used multiplex primers and Ion Reporter™ to analyze clonotyping and clonal lineage, whereby clonal lineages were defined as sets of unique rearrangements having a shared variable and joining gene, the same CDR3 length, and a minimum CDR3 nucleotide similarity of 85%. Ongoing CSR was defined as the presence of immunoglobulin (IgE0 M/D and at least one switched isotype (IgG, IgA, or IgE) or a combination of switched isotypes within the same lineage. The investigators defined ongoing SHM as the presence of subclones that differ within the VDJ region sequence compared with other clonal lineage members.
Among 57 cases showing no evidence of ongoing CSR or SHM, the investigators observed through variable gene mutation analysis the presence of three distinct subgroups having either no SHM, intermediate SHM (average 98% sequence identity) or high SHM (<94% identity). The results showed that three of four SMZ cases exhibited evidence of ongoing CSR or SHM.
“These results reveal previously underappreciated heterogeneity within CLL and suggest the subdivision of CLL based on a combination of immunoglobulin heavy chain mutation level and presence of ongoing SHM or CSR,” the authors concluded. They added the “described heterogeneity may serve as a valuable criterion for stratifying [patients with] CLL in the future.”
Looney T, et al. Clonal Lineage Analysis of CLL Research Samples by IGH Chain Sequencing to Reveal Novel CLL Subgroups Defined by Ongoing Class-Switch Recombination and Somatic Hypermutation. Presented at the 2020 ASCO Virtual Scientific Program; May 29-31, 2020.