title: 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.
abstract: 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.
authors.forename: Wenli
authors.initials: W
authors.lastname: Cui
authors.forename: Ying
authors.initials: Y
authors.lastname: Cai
authors.forename: Weige
authors.initials: W
authors.lastname: Wang
authors.forename: Zebing
authors.initials: Z
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Rui
authors.initials: R
authors.lastname: Bi
authors.forename: Weixiang
authors.initials: W
authors.lastname: Chen
authors.forename: Menghong
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pathology, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai 200032, PR China. xyzhou100@yahoo.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D056915:DNA Copy Number Variations / Q000235:genetics*; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt