IgCaller for reconstructing immunoglobulin gene rearrangements and oncogenic translocations from whole-genome sequencing in lymphoid neoplasms

Abstract

Immunoglobulin (Ig) gene rearrangements and oncogenic translocations are routinely assessed during the characterization of B cell neoplasms and stratification of patients with distinct clinical and biological features, with the assessment done using Sanger sequencing, targeted next-generation sequencing, or fluorescence in situ hybridization (FISH). Currently, a complete Ig characterization cannot be extracted from whole-genome sequencing (WGS) data due to the inherent complexity of the Ig loci. Here, we introduce IgCaller, an algorithm designed to fully characterize Ig gene rearrangements and oncogenic translocations from short-read WGS data. Using a cohort of 404 patients comprising different subtypes of B cell neoplasms, we demonstrate that IgCaller identifies both heavy and light chain rearrangements to provide additional information on their functionality, somatic mutational status, class switch recombination, and oncogenic Ig translocations. Our data thus support IgCaller to be a reliable alternative to Sanger sequencing and FISH for studying the genetic properties of the Ig loci.

mmsig: a fitting approach to accurately identify somatic mutational signatures in hematological malignancies

“…This sample had an estimated SBS9 contribution of 30% (95% CI 27–34%) and 1.7% of the bases in IGHV were mutated by Sanger sequencing. Unmutated IGHV status was confirmed by the novel algorithm IgCaller applied to WGS data 32 . This patient had been classified as memory-CLL based on the epigenetic profile, consistent with having passed through the germinal center 30 .…”

IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics

“…Immunoglobulin gene rearrangements and mutational status were obtained from WGS and WES using our recently described algorithm, IgCaller (version 1.1), 22 and RNA-seq using MiXCR (version 3.0.12). 23 The rearrangements obtained were verified on the Integrative Genomics Viewer.…”

How Chaotic Is Genome Chaos?

“…Adaptive immune system DNA changes. Restricted to lymphatic tissues and their cancers, where B cell lymphoma accounts for 95% of all lymphomas [ 37 ], these dedicated natural genetic engineering activities have evolved to generate antibody diversity by VDJ joining, antibody affinity maturation by somatic hypermutation (SH), and targeting of high affinity antibodies to different tissues by heavy chain class switch recombination (CSR) [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In VDJ joining to construct the variable region exons encoding the amino-terminal portion of antibody light and heavy chains are assembled by controlled chromosome breakage and joining reactions in primary B cells.…”

“…The involvement of the immunoglobulin loci IGH on chromosome 14, IGK on chromosome 2, and IGL on chromosome 22 as hotspots for recurring translocations activating different oncogenes has been evident for many years [ 145 , 146 ] Genetic experiments in mice provided evidence that the RAG2 subunit of the VDJ recombinase is required for oncogenic translocations [ 147 ]. A recent paper characterized the frequency and locations of inter-chromosomal oncogenic rearrangements involving IGH , IgK and IgL in different B cell-derived tumors: 6.5% for chronic lymphocytic leukemia (CLL), 98% for mantle cell lymphoma (MCL), 50% for multiple myeloma (MM), and 47% for diffuse large B cell lymphoma (DLBCL) [ 44 ]. Many of the following rearrangements were recurring both at the genetic locus target level and across tumor types: 7 examples of IGH - BCL2 in CLL; 62 examples of CCND1 - IGH in MCL; 7 examples of CCND1 - IGH , 4 of MYC - IG ), and 2 of NSD2 - IGH in MM; 22 IGH - BCL2 and 5 BCL6 - IGH in DLBCL.…”