Primary mediastinal large B‐cell lymphoma is characterized by large‐scale copy‐neutral loss of heterozygosity

• DOI: 10.1002/gcc.23069
• Publication Date: 2022-05-25T12:21:41Z
• Authors: Stefania Tuveri; Koen Debackere; Lukas Marcelis; Nicolas Dierckxsens; Jonas Demeulemeester; Eftychia Dimitriadou; Daan Dierickx; Pierre Lefesvre; Karen Deraedt; Carlos Graux; Lucienne Michaux; Jan Cools; Thomas Tousseyn; Joris Robert Verm...; Iwona Wlodarska
• Keywords: CN-LOH; 0301 basic medicine; Lymphoma, Large B-Cell, Diffuse/diagnosis; driver genes; primary mediastinal B-cell lymphoma; Loss of Heterozygosity; Genomics; mutations; SNPa; Mediastinal Neoplasms; Cancérologie; 03 medical and health sciences; whole exom/genome sequencing; Mediastinal Neoplasms/genetics; Mutation; genomics; Humans; loss of heterozygosity; Lymphoma, Large B-Cell, Diffuse; mutation; Biologie; Primary mediastinal B-cell lymphoma

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss heterozygosity (CN-LOH) landscape PMBL which distinguishes this tumor from other malignancies, including the biologically related diffuse large lymphoma. Using single nucleotide polymorphism array analysis we identified large-scale CN-LOH lesions in 91% (30/33) diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, cohort showed 157 extra-large (25.3-248.4 Mb) affecting up to 14 chromosomes per case (mean 4.4) resulting reduction an average 9.9% (range 1.3-51%) genome. Predominant involvement terminal chromosomal segments suggests implication specific crossover events pathogenesis PMBL. Notably, stretches non-randomly clustered on 6p (60%), 15 (37.2%), 17q (40%), frequently co-occurred with homozygous mutations MHC I (6p21), B2M (15q15), GNA13 (17q23) genes, respectively, as shown preliminary whole-exome/genome sequencing data. our findings implicate novel distinct mutational process contributing molecular The aberration acting "second hit" Knudson hypothesis, ranks major mechanism converting homozygosity PMBL-related driver genes. Screening 199 B leukemia/lymphoma whole-genomes revealed significant differences