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Acta Neuropathol Commun. 2019 Apr 29;7(1):66. doi: 10.1186/s40478-019-0720-8.

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

Author information

1
Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology, Boston, USA.
2
Department of Neurosurgery, Boston, USA.
3
Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 9E, Boston, MA, 02114, USA.
4
The University of Tokyo Hospital, Tokyo, Japan.
5
Present Address: Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
6
Present Address: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
7
Translational Research Laboratory, Cancer Center, Boston, USA.
8
Department of Pathology, Boston, USA.
9
Department of Neurosurgery, Boston, USA. cahill@mgh.harvard.edu.
10
Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 9E, Boston, MA, 02114, USA. cahill@mgh.harvard.edu.
11
Perlmutter Cancer Center, New York University Langone Health and School of Medicine, New York, USA. achi@neontherapeutics.com.
12
Present Address: Neon Therapeutics, 40 Erie Street, Suite 110, Cambridge, MA, USA. achi@neontherapeutics.com.

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.

KEYWORDS:

Dissemination; Glioblastoma; Gliomatosis; Multicentric; PIK3CA

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