Labreche Karim, Daniau Mailys, Sud Amit, Law Philip J, Royer-Perron Louis, Holroyd Amy, Broderick Peter, Went Molly, Benazra Marion, Ahle Guido, Soubeyran Pierre, Taillandier Luc, Chinot Olivier L, Casasnovas Olivier, Bay Jacques-Olivier, Jardin Fabrice, Oberic Lucie, Fabbro Michel, Damaj Gandhi, Brion Annie, Mokhtari Karima, Philippe Cathy, Sanson Marc, Houillier Caroline, Soussain Carole, Hoang-Xuan Khê, Houlston Richard S, Alentorn Agusti
Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.
(i) National Institute of Health and Medical Research (Inserm) U 1127, Paris, France, (ii) National Center for Scientific Research, Joint Research Unit 7225, Paris, France, (iii) Brain and Spine Institute (ICM), Paris, France, and (iv) Sorbonne University, Pierre and Marie Curie University, Paris 6, Paris, France.
Neuro Oncol. 2019 Aug 5;21(8):1039-1048. doi: 10.1093/neuonc/noz088.
Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.
We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.
We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.
To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.
原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的结外非霍奇金淋巴瘤。PCNSL是非霍奇金淋巴瘤的一种独特亚型，超过95%的肿瘤属于弥漫性大B细胞淋巴瘤（DLBCL）组。我们对免疫功能正常的患者进行了全基因组关联研究（GWAS），以探讨常见基因变异影响PCNSL发病风险的可能性。
我们对两项新的PCNSL全基因组关联研究进行了荟萃分析，共纳入475例病例和1134例欧洲血统对照。为了提高基因组分辨率，我们使用千人基因组计划并结合UK10K作为参考，对超过1000万个单核苷酸多态性进行了推算。此外，我们进行了转录因子结合破坏分析，并通过Capture Hi-C数据研究了局部染色质模式。
我们在3p22.1（rs41289586，ANO10，P = 2.17×10-8）和EXOC2附近的6p25.3（rs116446171，P = 1.95×10-13）鉴定出独立的风险位点。相比之下，rs41289586与DLBCL之间缺乏关联，这表明PCNSL和DLBCL存在不同的种系易感性。我们发现6p25.3（rs11646171）的非编码区域与IRF4启动子之间以及8q24.2（rs13254990）与MYC启动子之间存在环状染色质相互作用，这两个基因都与B细胞肿瘤发生密切相关。
据我们所知，这是第一项深入了解PCNSL遗传易感性研究。我们的发现代表了在确定常见基因变异对PCNSL发病风险的贡献方面迈出的重要一步。
