Immunoglobulin gene analysis in chronic lymphocytic leukemia in the era of next generation sequencing

Abstract

Twenty years after landmark publications, there is a consensus that the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is an important cornerstone for accurate risk stratification and therapeutic decision-making in patients with chronic lymphocytic leukemia (CLL). The IGHV SHM status has traditionally been determined by conventional Sanger sequencing. However, NGS has heralded a new era in medical diagnostics and immunogenetic analysis is following this trend. There is indeed a growing demand for shifting practice and using NGS for IGHV gene SHM assessment, although it is debatable whether it is always justifiable, at least taking into account financial considerations for laboratories with limited resources. Nevertheless, as this analysis impacts on treatment decisions, standardization of both technical aspects, and data interpretation becomes essential. Also, the need for establishing new recommendations and providing dedicated education and training on NGS-based immunogenetics is greater than ever before. Here we address potential and challenges of NGS-based immunogenetics in CLL. We are convinced that this perspective helps the hematological community to better understand the pros and cons of this new technological development for CLL patient management.

LYmphoid NeXt-Generation Sequencing (LYNX) Panel

“…Compared to other methods (both amplicon NGS and Sanger-based), it allowed the detection of rearrangements in all loci involved in the production of antigen receptors of B-and Tlymphocytes, not influenced by uneven amplification that has been noted in case of PCR-based methods. 63,64 Currently used approaches frequently omit some of IG/TR loci either due to technical difficulties in designing reliable primer assays (i.e. TRA locus) or the low added value of locus testing J o u r n a l P r e -p r o o f (e.g.…”

“…52 The assay can also be instrumental in the identification of multiclonal CLL, often constituting an interpretation challenge for a disease prognosis assessment but providing hints into the disease ontogeny. 34,36,54,64 The detection of lymphoma-specific translocations is important for lymphoma differential diagnosis and also provides additional markers for disease monitoring. 7 We assume that the LYNX panel is able to identify IGH translocations involving CCND1, BCL2, and MYC genes -the results were comparable with other methods, including FISH and long-range PCR.…”

Effectiveness of a Need-Based Program in Relieving Psychological Distress of Family Caregivers of Leukemia Patients: A Randomized Clinical Trial

“…The researchers of the present study created this need-based program with the view to focusing on developing and implementing procedures to support clients according to their requirements [14]. We actively supported the need-based program by responsive instruction, decisive intervention, and direct and indirect support [15]. Researchers of the present study, therefore, carried out this randomized clinical trial to examine the e cacy of the designed family-need-based program on relieving depression, anxiety, and stress of family caregivers of leukemia patients by meeting the speci c psychological needs of the caregivers.…”

Clonal dynamics in a composite chronic lymphocytic leukemia and hairy cell leukemia‐variant

“…In the majority of composite lymphomas, composed of two or more B‐cell non‐Hodgkin's lymphomas (NHLs), the components harbor different immunoglobulin heavy chain variable (IGHV) genes (defined as clonally unrelated lymphomas), whereas Richter syndrome consists of a transformation of CLL typically into a diffuse large B‐cell lymphoma with the same rearranged IGHV gene (ie, clones are related) 3,4 . Massively parallel sequencing of the IG receptor has allowed new insights into the clonal composition and subclonal architecture of CLL 5 . As an example, multiple productive clonally unrelated IGHV rearrangements have been detected by deep sequencing of IGH in ~25% of CLL cases 6 .…”

“…As an example, multiple productive clonally unrelated IGHV rearrangements have been detected by deep sequencing of IGH in ~25% of CLL cases 6 . The clinical implication of this finding has to be addressed in more detail 5 . Some of these cases may represent oligoclonal CLL; others may have a composite lymphoma as underlying cause.…”