Department of Neuropathology, University Hospital Cologne, 50924 Cologne, Germany.
Acta Neuropathol. 2010 Oct;120(4):529-35. doi: 10.1007/s00401-010-0709-7. Epub 2010 Jun 11.
Primary CNS lymphoma (PCNSL), the intracerebral subgroup of diffuse large B cell lymphoma (DLBCL), shows evidence for aberrant activation of the nuclear factor (NF)-kappaB pathway. In order to identify potential activators of the NF-kappaB complex, we analyzed the CARD11 and TNFAIP3 genes for the presence of somatic mutations and TNFAIP3 for aberrant promoter methylation in PCNSL. We also compared PCNSL to spinal DLBCL, because CARD11 and TNFAIP3 mutations have been described in systemic DLBCL. CARD11 mutations, located in the coiled-coil region, which may activate NF-kappaB, were detected in 16% (5/32) of PCNSL, while TNFAIP3 mutations were detected in 3% (1/32) of PCNSL. In PCNSL, all CARD11 mutations were heterozygous, in-frame, induced amino acid exchanges, and presumably led to activation of this oncogene. Spinal DLBCL harbored mutations of CARD11 and TNFAIP3 in 10% (1/10) and 20% (2/10) of cases, respectively. In both PCNSL and spinal DLBCL, mutations in CARD11 and TNFAIP3 were mutually exclusive. TNFAIP3 was unmethylated in all PCNSLs (30/30) and spinal DLBCLs (10/10). We conclude that mutations of the oncogene CARD11 may contribute to NF-kappaB activation and thereby play a role in the pathogenesis of PCNSL, while, in contrast to systemic DLBCL, inactivation of TNFAIP3 either by mutation or methylation seems to be of minor significance.
原发性中枢神经系统淋巴瘤（PCNSL）是弥漫性大 B 细胞淋巴瘤（DLBCL）的颅内亚型，其表现出核因子（NF）-kappaB 途径异常激活的证据。为了鉴定 NF-kappaB 复合物的潜在激活剂，我们分析了 CARD11 和 TNFAIP3 基因是否存在体细胞突变，以及 PCNSL 中 TNFAIP3 是否存在异常启动子甲基化。我们还将 PCNSL 与脊髓 DLBCL 进行了比较，因为 CARD11 和 TNFAIP3 突变已在系统性 DLBCL 中被描述。位于卷曲螺旋区的 CARD11 突变，可能激活 NF-kappaB，在 16%（5/32）的 PCNSL 中被检测到，而 TNFAIP3 突变在 3%（1/32）的 PCNSL 中被检测到。在 PCNSL 中，所有 CARD11 突变均为杂合、框内、诱导氨基酸交换，并且推测导致了该癌基因的激活。脊髓 DLBCL 中 CARD11 和 TNFAIP3 的突变分别在 10%（1/10）和 20%（2/10）的病例中被检测到。在 PCNSL 和脊髓 DLBCL 中，CARD11 和 TNFAIP3 的突变是相互排斥的。在所有 PCNSL（30/30）和脊髓 DLBCL（10/10）中，TNFAIP3 均未发生甲基化。我们的结论是，癌基因 CARD11 的突变可能有助于 NF-kappaB 的激活，从而在 PCNSL 的发病机制中发挥作用，而与系统性 DLBCL 相反，TNFAIP3 的失活无论是通过突变还是甲基化似乎都不重要。
