TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases
TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases
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DOI：
10.1111/j.1365-2141.2012.09243.x
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发表时间：
2012-09-01
影响因子：
6.5
通讯作者：
Miles, Rodney R.
中科院分区：
文献类型：
--
作者：
Leventaki, Vasiliki;Rodic, Vladimir;Miles, Rodney R.
TP53 (p53) 通路可通过 TP53 突变或缺失或 MDM2 过表达来抑制。两者均发生在伯基特淋巴瘤 (BL) 中，但许多病例缺乏其中任何一种异常。 BL 中尚未报道 TP53 抑制剂 MDM4 的表达模式，在没有 TP53 或 MDM2 异常的情况下，增加 MDM4 可能会解除对 TP53 通路的调节。我们通过研究 MDM4、MDM2 和 CDKN1A (p21) 蛋白和 mRNA 表达，研究了儿科 BL 患者样本 (n = 30) 中 TP53 通路的破坏情况； TP53突变； TP53蛋白表达；和基因拷贝数异常。 MDM4蛋白在30/30的肿瘤中表达，MDM2蛋白在7/30（23%）的肿瘤中弱表达。所有病例CDKN1A蛋白均为阴性，CDKN1A mRNA水平下降。 5/28 (18%) 病例中检测到 TP53 突变，并通过测序证实。 TP53 蛋白在 15/30 (50%) 病例中表达，其中 7/8 存在 TP53 基因改变。 MDM2 蛋白和 mRNA 表达水平与 TP53 基因变化或 TP53 蛋白表达缺失无关；然而，可检测的 TP53 蛋白表达与 MDM4 拷贝数增益和 mRNA 表达之间存在反比关系。 TP53 通路在儿科 BL 病例中失调，MDM4 表达增加可能是某些病例的主要机制。
The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases.