BioProject

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. More...

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. Overall design: 33 primary tumor samples and two cell lines Less...