The Topology of Myc Rearrangements in Double‐hit Lymphoma Is Constrained by the Preceding Igh‐bcl2 Rearrangement – an Llmpp Project
Year: 2021
Type: article
Study design: Observational Study
Abstract: Introduction: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) are aggressive tumors with poor prognosis. In virtually all HGBL-DH/TH-BCL2 tumors, BCL2 is rearranged to the variable region of the IGH locus, which is thought to occur early in B-cell differentiation during RAG-mediated VDJ recombination, leading to constitutive overexpression of BCL2 driven by the potent IGH Eµ enhancer. We explored the topology of MYC rearrangements in double-hit lymphomas compared with Burkitt lymphoma (BL) and MYC single-hit diffuse large B-cell lymphoma (DLBCL), to reveal patterns imposed by the preceding IGH-BCL2 rearrangement. Methods: We identified 112 HGBL-DH/TH-BCL2 and 55 de novo DLBCL MYC single-hit by break-apart fluorescence in situ hybridization, and included 96 MYC-rearranged BL tumors as a comparison group. A combination of whole genome and capture sequencing was used to identify MYC, BCL2 and BCL6 breakpoint sequences. Sequencing data were aligned to hg38 with bwa-mem, and structural variants were called using Manta, GRIDSS, and Delly. RNAseq data were quantified with Salmon and normalized with variance stabilizing transformation to interrogate MYC expression levels. Results: The MYC breakpoint sequence was recovered in 77% of tumors. Among BL and single-hit DLBCL tumors, over 80% of MYC rearrangements have an IGH partner, and less than 10% are partnered with IGL, IGK, or non-IG loci (Figure 1). In contrast, only 35% of MYC rearrangements in HGBL-DH/TH-BCL2 have an IGH partner, while 21% have IGL and 40% have non-IG partners (Figure 1). We show that MYC expression is comparable among all IG and most recurrent non-IG partners. Strikingly, in HGBL-DH/TH-BCL2 with IGH-MYC, the rearrangement involved the previously rearranged IGH-BCL2 allele, and the breakpoints exclusively localized to the recipient switch regions. This rearrangement leaves an intact Eµ enhancer in proximity to BCL2 on a doubly rearranged IGH allele while leaving the second IGH allele intact. In contrast, in BL and single-hit DLBCL the IGH-MYC breaks were equally distributed to Sµ (the donor IGHM switch region) and the recipient switch regions. MYC expression was equivalent in tumors with Sµ and recipient switch region breakpoints. Keywords: Genomics, Epigenomics, and Other -Omics, Aggressive B-cell non-Hodgkin lymphoma, Pathology and Classification of Lymphomas No conflicts of interests pertinent to the abstract.
Source: Hematological Oncology
DOI: 10.1002/hon.64_2879
Authors: L. K. Hilton, B. Collinge, S. Ben‐Neriah, B. M. Grande, G. W. Slack, P. Farinha, T. Miyata‐Takata, J. R. Cook, G. Ott, A. Rosenwald, E. Campo, C. Amador, T. C. Greiner, P. W. Raess, J. Y. Song, G. Inghirami, E. S. Jaffe, D. D. Weisenburger, W. C. Chan, H. Holte, K. Beiske, K. Fu, J. Delabie, S. Pittaluga, A. L. Feldman, L. H. Sehn, K. J. Savage, A. J. Mungall, L. M. Staudt, C. Steidl, L. M. Rimsza, R. D. Morin, D. W. Scott
Institutions: BC Cancer Agency, Sage Bionetworks, Niigata University, Cleveland Clinic, Robert Bosch Hospital, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Würzburg, Hospital Clínic de Barcelona, University of Nebraska Medical Center, Oregon Health & Science University, City Of Hope National Medical Center, Weill Cornell Medicine, National Cancer Institute, Oslo University Hospital, Roswell Park Comprehensive Cancer Center, University Health Network, University of Toronto, Mayo Clinic, Canada's Michael Smith Genome Sciences Centre, Center for Cancer Research, Mayo Clinic in Arizona, Simon Fraser University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3176971712