Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung

Abstract

The aim of the study was to investigate how alterations in the PI3K pathway correlate with non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation and protein expression of INPP4B, protein expression of pAkt, PDPK1, and PTEN and mutational status of PIK3CA and PTEN in 180 cases. Nineteen% displayed loss of INPP4B copy, whereas 47% lacked expression, both showing correlation with SCC. Elevated pAkt expression was seen in 63% of all cases, also correlating to SCC. PDPK1 was expressed in 70%, more in male than female patients. Regarding PTEN, 50% displayed loss of expression, of which seven were identified with mutations in the phosphatase domain. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC. When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA. Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression. As comparison, we also analyzed mitogen-activated protein kinase (MAPK) pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. No association was found to the Gly972Arg polymorphism of IRS-1, involved in activation of both PI3K and MAPK pathways. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of SCC of the lung.

Keywords: INPP4B; MAPK pathway; PI3K; non-small cell lung cancer; squamous cell carcinoma.

Figure 1

(A–L) INPP4B, PTEN, PDPK1, and pAkt expression and corresponding control tissue. (A) INPP4B positive expression in SCC, graded as ++ showing strong cytoplasmic staining, (B) INPP4B negative expression in SCC, (C) INPP4B negative control in skeletal muscle, (D) PTEN positive expression in SCC, (E) PTEN negative expression in SCC, (F) PTEN negative control with blocking peptide in human prostate, (G) PDPK1 positive expression in SCC, graded as +++ showing strong cytoplasmic and membrane expression, (H) PDPK1 negative expression in SCC, (I) PDPK1 negative control in breast cancer, (J) pAkt positive expression in SCC, graded as +++ showing strong cytoplasmic and nuclear expression, (K) pAkt negative expression in ADCA, and (L) pAkt negative control in breast cancer. Photographs were taken at 40× magnification. ADCA, adenocarcinoma; SCC, squamous cell carcinoma.