Abstract
Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients’ outcomes.
Highlights
The incidence of gastric cancer has continued to decline worldwide, it remains the fourth most common cancer and the second most common cause of cancer death worldwide [1]
This study presents the genetic profiles of PI3K/ AKT pathway components and the association of genetic mutations in this pathway with the clinicopathological characteristics, initial recurrence patterns and prognoses of gastric cancer patients
Our novel findings showed that intestinal-type gastric cancer with PI3K/AKT pathway mutations was associated with tumors in the lower-third of the stomach, whereas diffuse-type gastric cancer with PI3K/AKT pathway mutations was associated with tumors www.impactjournals.com/oncotarget
Summary
The incidence of gastric cancer has continued to decline worldwide, it remains the fourth most common cancer and the second most common cause of cancer death worldwide [1]. It is known that the accumulation of genetic alterations leads to the development of gastric carcinoma [3]. Most of the genetic mutations in gastric carcinoma correlate with changes in biological signals, such as those in the phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin pathway (PI3K/AKT/mTOR pathway) [4]. Little substantial evidence exists regarding whether the PI3K/AKT pathway is frequently altered in gastric carcinomas, its precise function remains to be determined [5,6,7]. An understanding of the biological pathways leading to the development of gastric carcinoma will provide an opportunity to improve targeted therapies
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