PI3K/AKT 通路的频繁拷贝数变异和 PI3K 亚基的异常蛋白表达与弥漫性大 B 细胞淋巴瘤的不良生存相关。
Frequent copy number variations of PI3K/AKT pathway and aberrant protein expressions of PI3K subunits are associated with inferior survival in diffuse large B cell lymphoma.
机构信息
Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, PR China.
出版信息
J Transl Med. 2014 Jan 13;12:10. doi: 10.1186/1479-5876-12-10.
BACKGROUND
It has been reported that the PI3K/AKT signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL), PI3K constitutive activation plays a crucial role in PI3K/AKT pathway. However, the copy number variations (CNVs) of PI3K subunits on gene level remain unknown in DLBCL. Therefore, the aim of the study is to investigate the CNV of PI3K subunits and their relationship with clinicopathological features exploring the possible mechanism underlying of PI3K activation in DLBCL.
METHODS
CNV of 12 genes in the PI3K/AKT pathway was detected by NanoString nCounter in 60 de novo DLBCLs and 10 reactive hyperplasia specimens as controls. Meanwhile, immunohistochemistry (IHC) was performed to examine the expression of p110α, p110β, p110γ, p110δ, and pAKT on DLBCL tissue microarrays.
RESULTS
All PI3K and AKT subunits, except for PIK3R1, had various CNVs in the form of copy number amplifications and copy number losses. Their rates were in the range of 8.3-20.0%. Of them PIK3CA and PIK3CB gene CNVs were significantly associated with decreased overall survival (P = 0.029 and P = 0.019, respectively). IHC showed that the frequency of strong positive expression of p110α, p110β, p110γ, and p110δ were 26.7%, 25.0%, 18.3%, and 25.0% respectively, and they were found to be associated with decreased survival (P = 0.022, P = 0.015, P = 0.015, and P = 0.008, respectively). Expression of p110α was not only significantly associated with CNVs of PIK3CA (P = 0.002) but also positively correlated with strong positive expression of pAKT (P = 0.026).
CONCLUSIONS
CNV of PIK3CA is highly associated with aberrant p110α protein expression and subsequent activation of PI3K/AKT pathway. CNVs of PIK3CA and PIK3CB, and aberrant protein expression of p110 isoforms are of great important value for predicting inferior prognosis in DLBCL. Frequent CNVs of PI3K/AKT subunits may play an important role in the tumorigenesis of DLBCL.
背景
已有报道称，PI3K/AKT 信号通路在弥漫性大 B 细胞淋巴瘤（DLBCL）中被激活，PI3K 的组成性激活在 PI3K/AKT 通路中起着至关重要的作用。然而，在 DLBCL 中，PI3K 亚基的基因水平上的拷贝数变异（CNVs）仍然未知。因此，本研究旨在探讨 PI3K 亚基的 CNV 及其与临床病理特征的关系，以探索 PI3K 在 DLBCL 中激活的潜在机制。
方法
通过 NanoString nCounter 在 60 例初发 DLBCL 和 10 例反应性增生标本中检测 PI3K/AKT 通路中的 12 个基因的 CNV。同时，在 DLBCL 组织微阵列上进行免疫组织化学（IHC）检测以检查 p110α、p110β、p110γ、p110δ 和 pAKT 的表达。
结果
所有 PI3K 和 AKT 亚基，除了 PIK3R1 外，均以拷贝数扩增和拷贝数缺失的形式出现不同的 CNV。它们的比率在 8.3-20.0%之间。其中，PIK3CA 和 PIK3CB 基因的 CNV 与总生存期降低显著相关（P=0.029 和 P=0.019）。IHC 显示，p110α、p110β、p110γ 和 p110δ 的强阳性表达频率分别为 26.7%、25.0%、18.3%和 25.0%，且与生存期降低相关（P=0.022、P=0.015、P=0.015 和 P=0.008）。p110α 的表达不仅与 PIK3CA 的 CNV 显著相关（P=0.002），而且与 pAKT 的强阳性表达呈正相关（P=0.026）。
结论
PIK3CA 的 CNV 与异常的 p110α 蛋白表达和随后的 PI3K/AKT 通路激活高度相关。PIK3CA 和 PIK3CB 的 CNV 以及 p110 同工型的异常蛋白表达对预测 DLBCL 的不良预后具有重要价值。PI3K/AKT 亚基的频繁 CNV 可能在 DLBCL 的肿瘤发生中起重要作用。
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