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

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss of heterozygosity (CN-LOH) landscape of PMBL which distinguishes this tumour from other B cell malignancies, including the biologically related diffuse large B-cell lymphoma. Using Single Nucleotide Polymorphism array analysis we identified large-scale CN-LOH lesions in 90.9% (30/33) of diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, the cohort showed 157 extra-large (25.3-248.4 Mb) CN-LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3-50.7%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B-cell specific crossover events in the pathogenesis of PMBL. Notably, CN-LOH stretches non-randomly clustered on chromosome 6p (60%), 15 (37.2%) and 17q (40%), and frequently co-occurred with homozygous mutations in MHC I (6p21), B2M (15q15) and GNA13 (17q23) genes, respectively, as yielded by preliminary whole-exome/genome sequencing data. Altogether, our findings implicate CN-LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as ‘second hit’ in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL-related driver genes.

原发性纵隔大B细胞淋巴瘤（primary mediastinal B-cell lymphoma, PMBL）的发生由累积性基因组畸变所驱动。我们发现PMBL具有独特的拷贝中性杂合性缺失（copy-neutral loss of heterozygosity, CN-LOH）谱型，该特征可将此肿瘤与其他B细胞恶性肿瘤相区分，包括生物学关联的弥漫大B细胞淋巴瘤（diffuse large B-cell lymphoma）。通过单核苷酸多态性（Single Nucleotide Polymorphism, SNP）芯片分析，我们在90.9%（30/33）的确诊PMBL病例以及所研究的两株PMBL来源细胞系中均检测到大规模CN-LOH病变。总体而言，该研究队列共检出157个超大尺寸（25.3~248.4 Mb）的CN-LOH病变，每例病例可累及多达14条染色体（平均4.4条），并使基因组平均9.9%（范围1.3%~50.7%）的区域杂合性水平下降。染色体末端区段的优先受累提示B细胞特异性交叉互换事件可能参与PMBL的发病机制。值得注意的是，CN-LOH区域非随机地聚集于6p（60%）、15（37.2%）和17q（40%）染色体上，且分别常与MHC I（6p21）、B2M（15q15）及GNA13（17q23）基因的纯合突变共存，该结论来自初步的全外显子组/全基因组测序（whole-exome/genome sequencing）数据。综上，我们的研究结果表明CN-LOH是一种全新且独特的突变过程，参与PMBL的分子发病机制。该畸变作为克努森假说（Knudson hypothesis）中的‘二次打击’事件，是将PMBL相关驱动基因转化为纯合状态的主要机制。