Primary mediastinal large B-cell lymphoma is hallmarked by large-scale copy-neutral loss of heterozygosity

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. It is unknown whether copy-neutral loss of heterozygosity (CN-LOH) contributes to the pathogenesis of this tumor. To get insight into the CN-LOH landscape of PMBL, we performed Single Nucleotide Polymorphism array (SNPa) analysis of two PMBL-derived cell lines and 33 primary tumors. The study uncovered large-scale CN-LOH lesions in both cell lines and 90.9% (30/33) of primary tumors. The latter cases showed 133 CN-LOH stretches of size >25Mb which affected up to 14 chromosomes per case (mean of 4.4). Involvement of chromosomal segments was predominant (81.2%), which, in a heterozygous diploid context, suggests the implication of B-cell specific crossover events. Further analysis indicated that the CN-LOH lesions were triggered by one or two consecutive molecular hits. Notably, CN-LOH segments were non-randomly clustered on chromosome 6p (60%), 15 (37.2%) and 17q (40%). Preliminary whole-exome sequencing data yielded coincidence of these lesions with mutations in MHC I and histon-related genes (6p21), B2M (15q15) and GNA13 (17q23), respectively. We hypothesize that CN-LOH-associated hits occurred early during lymphomagenesis, following mutagenesis but preceding genomic gains. Screening of the cohort of 2,658 cancer whole-genomes revealed that the CN-LOH landscape in PMBL is unique and distinguishes this tumor from other malignancies. Altogether, CN-LOH lesions rank as the most frequent genetic defect identified so far in this disease and the CN-LOH landscape suggest a hitherto undescribed mitotic recombinational driver. The aberrations affect the expression of key driver genes and functionally alternate genomic deletions which are infrequent in PMBL. 33 primary tumor samples and two cell lines