Mutations in PI3K/AKT pathway genes and amplifications of PIK3CA are associated with patterns of recurrence in gastric cancers

// Wen-Liang Fang 1, 2 , Kuo-Hung Huang 1, 2, 3 , Yuan-Tzu Lan 2, 4 , Chien-Hsing Lin 5 , Shih-Ching Chang 2, 4, * , Ming-Huang Chen 2, 6 , Yee Chao 2, 6 , Wen-Chang Lin 7, 8 , Su-Shun Lo 2, 9 , Anna Fen-Yau Li 2, 10 , Chew-Wun Wu 1, 2 , Shih-Hwa Chiou 3, 11, 12 , Yi-Ming Shyr 1, 2, * 1 Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan 2 School of Medicine, National Yang-Ming University, Taipei City, Taiwan 3 Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei City, Taiwan 4 Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei City, Taiwan 5 Genome Research Center, National Yang-Ming University, Taipei City, Taiwan 6 Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 7 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 8 Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei, Taiwan 9 National Yang-Ming University Hospital, Yilan City, Taiwan 10 Department of Pathology, Taipei Veterans General Hospital, Taipei City, Taiwan 11 Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei City, Taiwan 12 Institute of Pharmacology, National Yang-Ming University, Taipei City, Taiwan * These authors have contributed equally to this work Correspondence to: Shih-Ching Chang, e-mail: changsc@vghtpe.gov.tw Yi-Ming Shyr, e-mail: ymshyr@vghtpe.gov.tw Keywords: PI3K/AKT pathway, PIK3CA amplifications, recurrence pattern, diffuse-type, prognosis Received: August 08, 2015      Accepted: December 05, 2015      Published: December 17, 2015 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.