Frequent Mutation of the PIK3CA Gene in Saudi Arabian Diffuse Large B-Cell Lymphoma.

Phosphotidylinositol 3′-kinases are lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, motility, and are implicated to play an important oncogenic role in many cancer types. The PIK3CA gene encodes the p110α catalytic subunit of PI3K-like gene. Recently, high frequencies of PIK3CA somatic mutations have been detected in various kinds of human cancers notably colorectal, gastric, and breast cancers. It has also been shown that somatic mutations in the PIK3CA gene have been associated with a higher expression of p-AKT in certain cancers. However, the role of PIK3CA mutations in hematological malignancies has not been elucidated in detail. Therefore, we tested whether PIK3CA is subject to mutations in diffuse large B-cell lymphoma (DLBCL). Exons 9 and 20, encoding the highly conserved helical and kinase domains of PIK3CA, which account for 85% of somatic mutation in PIK3CA gene, were subjected to direct sequencing analysis in 219 cases of DLBCL. Somatic missense mutations were observed in 17 of 212 (8%) DLBCL cases. Out of which, 10 mutations (60%) occurred at codon 1047 in the kinase domain, which is one of the previously reported hot spot within the PIK3CA gene. Additionally, a silent polymorphism (T1025T) was found in one of the DLBCL sample. Moreover, activation of AKT was observed in 14 out of 17 (82%) of the DLBCL harboring PIK3CA mutations. Further, 9 out of 17 cases showed high level of pAKT. Additionally, 12 out of 17 DLBCL patients with PIK3CA mutations showed over-expression of the proliferative marker Ki-67. Expression of high level of pAKT was significantly correlated with over-expression of Ki-67 (p=0.0097). Overall survival in DLBCL cases harboring PIK3CA mutation showed poor survival as compared to the DLBCL cases lacking mutations though it was not statistically significant. These data indicate that mutations of PIK3CA play an oncogenic role in DLBCL tumors and argue for a role of PIK3CA targeting in treatment of DLBCL patients.