It has been well documented that the PI3K/Akt pathway plays an important role in cancer-related functions of cell proliferation, catabolism, cell adhesion and apoptosis [10, 16, 17, 26, 27], and it has a crucial role in the tumorigenesis and pathogenesis of many human cancers. The previous studies have shown that PIK3CA, as a subunit of PI3K, is frequently mutated in various human cancers, such as ovarian, thyroid cancer, breast, cervical cancers, and pituitary tumors [10, 12, 13, 16, 17, 21, 28]. However, our study showed that the most common activating PIK3CA mutations reported in other cancers were not frequent in gastric cancer. Therefore, the PIK3CA mutations may not be a common mechnaism in the activation of PI3K/Akt signaling pathway. Instead, our study demonstrated PIK3CA gene was highly amplified in gastric cancer. Genomic amplification, rather than gene mutations, may represent another major signature of neoplastic transformation and tumor progression . Chromosome copy number abnormalities have been frequently identified in gastric cancer , including PIK3CA amplification .
Of particular interest was the PIK3CA amlification was closely associated with elevated p-Akt, suggesting that this genetic alteration could lead to oncogenic activation of PI3K/Akt signaling pathway and thus contributed to the malignant progression of gastric cancer. It was consistent with a previous study , which PIK3AC gene was aberrantly amplified, and mutually excluded with monallelic deletion of PTEN gene in gastric cancer, further supporting that PIK3CA amplification, like PTEN loss, might contribute to gastric tumorigenesis through the activation of the PI3K/Akt pathway.
Given PIK3CA mutations and amplification play the critical role in gastric tumorigenesis, we investigated their clinical significances and prognostic values in a large cohort of gastric cancer patients who had known survival data. Out data showed that PIK3CA mutations were not associated with most of clinicopathological characteristics and clinical outcome in gastric cancer. One possibility is the limited number of PIK3CA mutations found in this study. However, PIK3CA amplification was associated with a significantly increased risk of cancer-related death, and positively associated tumor differentiation. Most noteworthy, PIK3CA amplification significantly affected the overall prognosis in gastric cancer whatever the patients who had early-stage or late-stage tumors, suggesting that this genetic event plays an important role in the multistep process of gastric carcinogenesis. Taken together, PIK3CA amplification may be served as a potential prognostic marker for gastric cancer patients.
The prognostic markers may have another role in predicting and guiding the clinical treatment of cancer patients by allowing the identification of patients suited to current therapies. In this era of molecularly targeted therapy, inhibitors and antibodies targeting specific molecules are vigorously being developed, and some have been demonstrated to be effective in clinical settings, such as hematological malignancies  and non-small cell lung cancer (NSCLC) [33, 34]. Of interest, some of these targeted drugs are more effective against the genetically altered cancerous form of the target, as illustrated by the activities of gefitinib and erlotinib against the mutated EGFR present in NSCLC [33, 34], and the activity of trastuzumab against breast cancer with amplified ErbB2 . Mutations and amplification of certain kinases are involved in gastric tumorigenesis. However, only has trastuzumab, which is a monoclonal antibody targeting ErbB2, been recently approved as the first molecularly targetd drug against gastric cancer. The PI3K/Akt pathway is one of the most important signaling pathways in human carcinogenesis. In the present study, a high prevalence of PIK3CA amplification was found in gastric cancer, which was significantly associated with poor prognosis of gastric cancer patients. Importantly, PIK3CA amplification could aberrantly activate the PI3K/Akt signaling pathway. In addition, the drugs, such as mTOR and Akt inhibitors that target this signaling pathway, are being vigorously developed . Thus, for some gastric cancer patients harbored oncogenic alterations within the PI3K/Akt signaling pathway, such as PIK3CA amplification, combination therapy with an mTOR or Akt inhibitor should be considered.