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PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma

Leukemia volume 21, pages 2368–2370 (2007)Cite this article

Phosphatidylinositol 3 kinases (PI3Ks) are important regulators of cellular growth, transformation, adhesion, apoptosis, survival and motility.1 The activation of PI3K results in the generation of the second messenger, phosphatidylinositol 3,4,5 trisphosphate (PIP3) from phosphatidylinositol 4,5 bisphosphate (PIP2). PIP3 acts as an important second messenger lipid in tumorigenesis, by activating AKT and other pathways which inhibit apoptosis and promote cellular growth, proliferation, cell motility, angiogenesis whereas phosphatase and tensin homolog deleted on chromosome 10 (PTEN) catalyzes the precise opposite reaction, thereby reducing the pool of PIP3, inhibiting growth signals and suppressing tumor formation. One of the catalytic subunits of PI3K, the p110 catalytic subunit-α (PIK3CA), is a transforming oncogene,2 that was shown to have activating mutations in the commonly occurring cancers.3 Functional analysis of the common-hot spot PIK3CA mutations that have been done previously by performing experiments of overexpression as well as gene deletion using somatic cell knockouts, has demonstrated that these mutations are in fact oncogenic.2 The constitutive activation of the PI3K/AKT signaling pathway in a subset of mantle cell lymphoma that includes blastoid variants,4 and our recent findings of aberrant activation of the PI3K/AKT pathway in diffuse large B-cell lymphoma (DLBCL) have prompted us to study PTEN/PI3K/AKT pathway in the development and progression of DLBCL.5 We investigated in this study the existence of PIK3CA mutation in 215 DLBCL, immunohistochemical expression of PTEN and p-AKT, and described for the first time the significant correlation of PIK3CA mutations to clinical markers and its relationship to functional PTEN.

Next, PTEN protein expression was investigated by immunohistochemistry (IHC) on these 215 DLBCL samples using tissue microarray technology. Out of which, 76 DLBCL samples (37%) showed reduced or loss of PTEN expression (PTEN−). Correlation analysis between PIK3CA mutations and PTEN IHC status revealed a significant association, in that the majority of PIK3CA mutations were found in PTEN+ cases (P=0.0146), in concordance with an earlier report.6 This probably implies that de-regulated PIP3 is critical for lymphomagnesis in a significant fraction of DLBCL and that loss of PIP3 homeostasis by abrogation of either PIK3CA or PTEN relieves selective pressure for targeting other genes, similar observations were made by other authors.6, 7 Furthermore, 17 cases with PIK3CA mutations were screened for PTEN mutations. All nine exons of PTEN were sequenced and none of the DLBCL cases harboring PIK3CA mutations contained PTEN mutations. Although some recent studies have reported existence of double mutants for PIK3CA and PTEN in some tumors, our data excludes the possibility of coexistence of PTEN mutation with PIK3CA mutation as reported by Broderick et al.,7 who analyzed PIK3CA mutations in high-grade brain tumors. This might indicate that PIK3CA mutation is a potent activator of PI3K pathway by itself.

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Acknowledgements

We thank Azadali Moorji and Valerie Atizado for their technical services.

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Authors and Affiliations

  1. Department of Human Cancer Genomic Research, Research Centre, King Fahad National Center for Children's Cancer & Research, Riyadh, Saudi Arabia

    J Abubaker, P P Bavi, S Al-Harbi, A K Siraj, S Uddin & K Al-Kuraya

  2. Department of Pathology, King Faisal Specialist Hospital and Research center, Riyadh, Saudi Arabia

    F Al-Dayel

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  1. J Abubaker
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  2. P P Bavi
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Correspondence to K Al-Kuraya.

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Abubaker, J., Bavi, P., Al-Harbi, S. et al. PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma. Leukemia 21, 2368–2370 (2007). https://doi.org/10.1038/sj.leu.2404873

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