PIK3CA activating mutations are associated with more disseminated disease at presentation and earlier recurrence in glioblastoma

Shota Tanaka,Tracy T Batchelor,David N Louis,Dora Dias-Santagata,Andrew S Chi,Daniel P Cahill,Darrell R Borger,Leif W Ellisen,A John Iafrate,Daniel Yang

doi:10.1186/s40478-019-0720-8

Abstract

Phosphatidylinositol 3-kinase signaling promotes cell growth and survival and is frequently activated in infiltrative gliomas. Activating mutations in PIK3CA gene are observed in 6–15% of glioblastomas, although their clinical significance is largely undescribed. The objective of this study was to examine whether PIK3CA mutations are associated with a specific clinical phenotype in glioblastoma. We retrospectively reviewed 157 consecutive newly diagnosed glioblastoma patients from December 2009 to June 2012 who underwent molecular profiling consisting of targeted hotspot genotyping, fluorescence in situ hybridization for gene amplification, and methylation-specific PCR for O6-methylguanine-DNA methyltransferase promoter methylation. Molecular alterations were correlated with clinical features, imaging and outcome. The Cancer Genome Atlas data was analyzed as a validation set. There were 91 males; median age was 58 years (range, 23–85). With a median follow-up of 20.9 months, median progression-free survival (PFS) and estimated overall survival (OS) were 11.9 and 24.0 months, respectively. Thirteen patients (8.3%) harbored PIK3CA mutation, which was associated with younger age (mean 49.4 vs. 58.1 years, p = 0.02). PIK3CA mutation correlated with shorter PFS (median 6.9 vs. 12.4 months, p = 0.01) and OS (median 21.2 vs. 24.2 months, p = 0.049) in multivariate analysis. A significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions, was observed (46.2% vs. 11.1%, p = 0.004). In conclusion, despite the association with younger age, PIK3CA activating mutations are associated with earlier recurrence and shorter survival in adult glioblastoma. The aggressive course of these tumors may be related to their propensity for disseminated presentation.

Highlights

Recent years have witnessed a remarkable transformation in our understanding of glioma development and classification
As expected, established clinical prognostic factors such as age, Karnofsky performance status (KPS), and gross total resection (GTR) were associated with longer progressionfree survival (PFS) and/or overall survival (OS) in univariate analyses (Table 2)
We found a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as 6 of 13 (46.2%) PIK3CA mutant glioblastomas presented with dissemination compared to 16 of 144 (11.1%) PIK3CA wildtype tumors (p = 0.004)

Summary

Introduction

Recent years have witnessed a remarkable transformation in our understanding of glioma development and classification. It is recognized that gliomas consist of clinically distinct, molecularly-defined disease entities, with different entities often distinguished by somatic mutations in single genes [1,2,3]. These molecular subgroups are distinguishable by their biology and. Class IA phosphatidylinositol 3-kinase (PI3K) is activated in several cancer types by somatic activating hotspot mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene, which encodes the catalytic subunit p110α. Recurrent somatic mutations in PIK3CA and PIK3R1 were identified in 6–15 and 10% of glioblastomas, respectively [15, 16], which were accompanied by activated PI3K signaling [15]. We sought to determine whether somatic mutations in PIK3CA are associated with a distinct phenotype in patients with newly diagnosed glioblastoma

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