CLINICOPATHOLOGICAL AND MOLECULAR CORRELATES OF HER2 EXPRESSION, PIK3CA MUTATIONS AND EBV INFECTION INVOLVED IN THE PI3K-AKT PATHWAY IN GASTRIC CANCER

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Abstract

Background

We have characterized the molecular alterations in gastric cancers, especially those with MSI (Nature, Science, Nature Genetics 2006, 2009, Cancer Cell 2010). We have also reported the efficacy of molecular therapies targeting IGF1R in gastric cancer (Mol Cancer Ther 2008, Cancer 2010). Considerable attention has been given to the potential role of the PI3K-Akt signaling pathway in gastric cancer. This signal activation is thought to be one of the mechanisms underlying resistance to trastuzumab.

Aims

The aim of this study was to systematically characterize HER2 expression, PIK3CA mutations and EBV infection, all of which are involved in the PI3K-Akt-signaling pathway, in a large cohort of patients with gastric cancer to determine their prevalences with a high level of precision and to correlate them with clinicopathological and molecular features, such as MSI and pAkt expression.

Methods

We analyzed 231 T2–T4 gastric cancer tissues. Expression of HER2 and pAkt was analyzed by immunohistochemistry. PIK3CA mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. EBV infection was analyzed by ISH.

Results

HER2 overexpression (IHC 3+) was present in 20 samples (8.4%) and it was significantly correlated with intestinal histological type (P = 0.05) and pAkt expression. PIK3CA mutations were present in 20 cases (8.4%) and it was significantly correlated with MSI (P < 0.01). The mutation frequency was high (21%) in T4 cancers and low (6%) in T2 cancers. Importantly, two new types of mutation, R88Q and R108H, were found in exon 1. The frequency of pAkt expression was higher in cancers with exon 20 mutations (100%) than in those with exon 1 (40%) or exon 9 (56%) mutations. In survival analysis, pAkt expression was significantly correlated with poor prognosis (P = 0.02).

Conclusions

HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized in relation to Akt activation. pAkt expression was significantly correlated with poor prognosis and HER2 expression. The results have potential clinical implications since the mutational status of PIK3CA could stratify patients for genotype-based molecular therapy targeting the HERs-PI3K pathway. We will discuss the next-generation strategies including anti-IGF1R for molecular targeted therapy for gastric cancer.

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