Genomic characterization of primary central nervous system lymphoma
Genomic characterization of primary central nervous system lymphoma
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DOI：
10.1007/s00401-016-1536-2
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发表时间：
2016-06-01
影响因子：
12.7
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Fukumura, Kazutaka;Kawazu, Masahito;Mano, Hiroyuki
原发性中枢神经系统淋巴瘤（PCNSL）是一种局限于中枢神经系统（CNS）的罕见恶性肿瘤，大多数PCNSL在病理学上属于弥漫性大B细胞淋巴瘤（DLBCL）。我们现已对 41 个 DLBCL 型 PCNSL 肿瘤组织和配对正常标本进行了全外显子组测序，并对 30 个肿瘤进行了 RNA 测序，揭示了 PIM1 (100 %)、BTG2 (92.7 %) 和 MYD88 (85.4 %) 中非同义体细胞突变的频率非常高。 NF-κ B 通路中的许多基因在同一肿瘤内同时发生突变。此外，HLA 基因的局灶性缺失或体细胞突变与不良预后相关。研究发现，染色体 7q35 基因的拷贝数扩增和过度表达也可预测短期无进展生存期。还检测到 GRB2 的致癌突变，其在培养细胞中的影响被下游激酶 MAP2K1 和 MAP2K2 的抑制剂减弱。患有 MYD88 突变阳性的肿瘤个体在外周血单核细胞中也以较低频率存在相同的突变，这表明 MYD88 突变阳性的癌前细胞起源于中枢神经系统之外，并在额外的基因打击后发展成淋巴瘤，从而适应中枢神经系统环境。
Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-kappa B pathway are concurrently mutated within the same tumors. Further, focal deletion or somatic mutations in the HLA genes are associated with poor prognosis. Copy number amplification and overexpression of genes at chromosome 7q35 were both found to predict short progression-free survival as well. Oncogenic mutations in GRB2 were also detected, the effects of which in cultured cells were attenuated by inhibitors of the downstream kinases MAP2K1 and MAP2K2. Individuals with tumors positive for MYD88 mutations also harbored the same mutations at a low frequency in peripheral blood mononuclear cells, suggesting that MYD88 mutation-positive precancerous cells originate outside of the CNS and develop into lymphoma after additional genetic hits that confer adaptation to the CNS environment.