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.

Highlights

  • 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)

  • IgCaller produces a preliminary analysis of the functionality of the rearranged sequences, these sequences can be used as input of downstream programs such as IMGT/V-QUEST or IgBLAST, as usually done for the sequences obtained from Sanger sequencing (SSeq)/next-generation sequencing (NGS) (Fig. 1a)

  • We describe that the rearranged Ig genes of B cell neoplasms, including class switch recombination (CSR) and oncogenic Ig translocations, can be fully reconstructed from short-read whole-genome sequencing (WGS) data

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Summary

Introduction

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). 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. 8 Department of Mature normal and tumor B cells express a unique immunoglobulin (Ig) gene rearrangement This individual Ig gene is formed during the first steps of B cell development in the bone marrow where both heavy (IGH) and light chains [kappa (IGK) or lambda (IGL)] are rearranged by a hierarchical process in which distant variable (V), diversity (D, only in the IGH locus), and joining (J) genes are joint through deletions of the genomic sequence between them[1]. We demonstrat the accuracy of IgCaller using WGS data of 404 B cell neoplasms with available SSeq/NGS of the IGH V(D)J and/or IGLC and isotype expression for comparison: 230 cases of CLL in two independent cohorts of 152 (cohort 1 [C1])[18,19] and 78 (cohort 2 [C2]), 64 cases of MCL20, 30 MM21, 73 DLBCL22, and 7 mature B cell nonHodgkin lymphomas (B-NHL) (Supplementary Data 1)

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