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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0167v1 16/1/301    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lin, Y. Articles by Lu, Y. Search for Related Content PubMed PubMed Citation Articles by Lin, Y. Articles by Lu, Y.

Y Lin, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China, Shanghai , 200040, China
X Jiang, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China, Shanghai, China
Y Shen, Institute of Endocrinology and Diabetologia, Fudan University, P. R. China, Shanghai, China
M Li, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China, Shanghai, China
H Ma, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China, Shanghai, China
M Xing, Division of Endocrinology and Metabolism, The Johns Hopkins University Schoo of Medicine, Baltimore, United States
Y Lu, Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, P. R. China, Shanghai, China

Correspondence: Yong Lin, Email: linyong7007{at}hotmail.com

Abstract

Genetic alterations in the PIK3CA gene of the phosphoinositide 3-kinase (PI3K)/AKT pathway have been found in many human tumors, but they have not been explored in pituitary tumors. We undertook the present study to explore mutations and amplifications of the PIK3CA gene in pituitary tumors. DNA sequencing and real-time quantitative PCR were used to examine mutations and amplifications, respectively, on genomic DNA samples isolated from 353 cases of pituitary tumors, and immunohistostaining was used to assess PIK3CA expression. Eight of 91 (9%) invasive pituitary tumors vs. 0 of 262 (0%) non-invasive tumors were found to harbor somatic mutations in exons 9 and 20 of the PIK3CA gene (P<0.001), and the mutation was associated with increased disease recurrence. Genomic PIK3CA amplifications (defined as > 4 copies) were observed in both invasive and noninvasive tumors, with a prevalence of around 20-40% in various types of pituitary tumors. PIK3CA protein overexpression was observed in cases with high PIK3CA copy number. Ras mutations were also examined and found in 6 of 91 (7%) invasive tumors. PIK3CA amplifications were mutually exclusive with PIK3CA or Ras mutations (P<0.001). This study demonstrated for the first time relatively common PIK3CA mutations and amplifications as well as Ras mutations and their tendency of mutual exclusivity in pituitary tumors. The data provide strong genetic evidence supporting a role of the PI3K/AKT signaling pathway in the tumorigenesis of pituitary tumors, particularly the invasive types.