Abstract
BackgroundIt 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.MethodsCNV 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.ResultsAll 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).ConclusionsCNV 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.
Highlights
It has been reported that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is activated in diffuse large B-cell lymphoma (DLBCL), PI3K constitutive activation plays a crucial role in PI3K/AKT pathway
Among genes with copy number variations (CNVs), we found that the copy numbers of PIK3CA, PIK3CB, PIK3R2, and PIK3C2B were only amplified (10/10, 12/12, 14/14, and 8/8, respectively); copy numbers of PIK3CG, PIK3C2A, PIK3C2G, AKT1, AKT2, and AKT3 were amplified in the majority of cases (4/5, 4/5, 11/12, 7/11, 8/11, and 11/13, respectively), whereas copy number losses occurred in fewer cases (1/5, 1/5, 1/12, 4/11, 3/11, and 2/13, respectively); copy number losses for PIK3CD occurred in the majority of cases (7/10), whereas amplifications occurred in a few cases (3/10) (Table 3)
In DLBCL, the CNV frequency of PI3K-AKT subunits was in the range of 1–10 genes; in one of the 60 DLBCLs, 10 different genes were detected with CNVs
Summary
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. Activated PI3K/AKT signaling pathways have been reported to be associated with decreased disease-free survival (DFS) and a poor response to treatment in patients with DLBCL [5]. This suggests that the PI3K/AKT pathway is potentially an important tumorigenic signaling route and an unfavorable prognostic factor in DLBCL
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