Abstract
BackgroundThe phosphoinositide 3-kinase (PI3K)/Akt pathway plays a fundamental role in cell proliferation and survival in human tumorigenesis, including gastric cancer. PIK3CA mutations and amplification are two major causes of overactivation of this pathway in human cancers. However, until this work, there was no sound investigation on the association of PIK3CA mutations and amplification with clinical outcome in gastric cancer, particularly the latter.MethodsUsing direct sequencing and real-time quantitative PCR, we examined PIK3CA mutations and amplification, and their association with clinicopathological characteristics and clinical outcome of gastric cancer patients.ResultsPIK3CA mutations and amplification were found in 8/113 (7.1%) and 88/131 (67%) gastric cancer patients, respectively. PIK3CA amplification was closely associated with increased phosphorylated Akt (p-Akt) level. No relationship was found between PIK3CA mutations and clinicopathological characteristics and clinical outcome in gastric cancer. PIK3CA amplification was significantly positively associated with cancer-related death. Importantly, Kaplan-Meier survival curves revealed that the patients with PIK3CA amplification had significantly shorter survival times than the patients without PIK3CA amplification.ConclusionsOur data showed that PIK3CA mutations were not common, but its amplification was very common in gastric cancer and may be a major mechanism in activating the PI3K/Akt pathway in gastric cancer. Importantly, Kaplan-Meier survival curves revealed that PIK3CA amplification was significantly positively associated with poor survival of gastric cancer patients. Collectively, the PI3K/Akt signaling pathway may be an effective therapeutic target in gastric cancer.
Highlights
The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a fundamental role in cell proliferation and survival in human tumorigenesis, including gastric cancer
The aberrant signaling of major pathways is involved in this process, including phosphoinositide 3-kinase (PI3K)/Akt pathway, which plays a fundamental role in cell proliferation and survival in gastric tumorigenesis [7,8,9]
With a gene copy number of 4 or more defined as amplification, we found the incidence of PIK3CA amplification in gastric cancers was 67% (88/131) in the present study, whereas no PIK3CA amplification was found in the 37 normal controls
Summary
The phosphoinositide 3-kinase (PI3K)/Akt pathway plays a fundamental role in cell proliferation and survival in human tumorigenesis, including gastric cancer. PIK3CA mutations and amplification are two major causes of overactivation of this pathway in human cancers. Until this work, there was no sound investigation on the association of PIK3CA mutations and amplification with clinical outcome in gastric cancer, the latter. The aberrant signaling of major pathways is involved in this process, including phosphoinositide 3-kinase (PI3K)/Akt pathway, which plays a fundamental role in cell proliferation and survival in gastric tumorigenesis [7,8,9]. PIK3CA overexpression caused by gene amplification increased PI3-kinase activity and phosphorylated Akt level, which was associated with aberrant cell proliferation and apoptosis, both of which are directly linked to tumorigenesis [16,17,20]
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