Data from <i>Phosphatidylinositol 3′-Kinase Catalytic Subunit α</i> Gene Amplification Contributes to the Pathogenesis of Mantle Cell Lymphoma

Abstract

<div>Abstract<p><b>Purpose:</b> Activation of phosphatidylinositol 3′-kinase pathway is implicated in the pathogenesis of mantle cell lymphoma (MCL). The genetic change in <i>phosphatidylinositol 3′-kinase catalytic subunit α</i> (<i>PIK3CA</i>) in MCL has not been identified.</p><p><b>Experimental Design:</b> Thirty-five primary MCL cases and 2 MCL cell lines (GRANTA-519 and Rec-1) were used to investigate somatic mutation and gene copy number of <i>PIK3CA</i>. Gene copy number was determined using quantitative real-time PCR and fluorescence <i>in situ</i> hybridization. We used quantitative real-time reverse transcription-PCR to measure <i>PIK3CA</i> transcription levels. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and phoshorylated AKT protein levels were analyzed using Western blotting and immunohistochemistry. Flow cytometry was used to assess apoptosis after treatment of MCL cell lines and one control cell line with LY294002, a specific inhibitor of PI3KCA.</p><p><b>Results:</b> Fifteen of 22 (68%) MCL cases and the MCL cell lines harbored a gain (≥3) of <i>PIK3CA</i> gene copy number. In addition, cases with increased <i>PIK3CA</i> gene copy number had elevated <i>PIK3CA</i> mRNA levels. Furthermore, amplification of <i>PIK3CA</i> correlated with the status of AKT phosphorylation in 7 of 12 (58%) primary MCL cases. Inhibition of <i>PIK3CA</i> induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by Western blotting, whereas 5 of 33 (15%) cases tested by immunohistochemistry had loss of PTEN expression.</p><p><b>Conclusions:</b> We conclude that a gain of gene copy number of <i>PIK3CA</i> is frequent genetic alteration that contributes to MCL progression. <i>PIK3CA</i> is a promising therapeutic target in MCL. (Clin Cancer Res 2009;15(18):5724–32)</p></div>