PIK3CA exon9 mutations associate with reduced survival, and are highly concordant between matching primary tumors and metastases in endometrial cancer

Siv Mjos,Gordon B Mills,Karl-Henning Kalland,Helga B Salvesen,Anna Berg,Camilla Krakstad,Anne M Oyan,Ingvild L Tangen,Jone Trovik,Erling A Hoivik,Mari K Halle,Even Birkeland,Kanthida Kusonmano,Frederik Holst,Aurélia E Lewis,Henrica M J Werner,Karen K Mauland

doi:10.1038/s41598-017-10717-z

Abstract

Mutations of the phosphoinositide-3-kinase (PI3K) catalytic subunit alpha gene (PIK3CA) are frequent in endometrial cancer. We sequenced exon9 and exon20 of PIK3CA in 280 primary endometrial cancers to assess the relationship with clinicopathologic variables, patient survival and associations with PIK3CA mRNA and phospho-AKT1 by gene expression and protein data, respectively. While PIK3CA mutations generally had no impact on survival, and were not associated with clinicopathological variables, patients with exon9 charge-changing mutations, providing a positive charge at the substituted amino acid residue, were associated with poor survival (p = 0.018). Furthermore, we characterized PIK3CA mutations in the metastatic setting, including 32 patients with matched primary tumors and metastases, and found a high level of concordance (85.7%; 6 out of 7 patients), suggesting limited heterogeneity. PIK3CA mRNA levels were increased in metastases compared to the primary tumors (p = 0.031), independent of PIK3CA mutation status, which rather associated with reduced PIK3CA mRNA expression. PIK3CA mutated tumors expressed higher p-AKT/AKT protein levels, both within primary (p < 0.001) and metastatic lesion (p = 0.010). Our results support the notion that the PI3K signaling pathway might be activated, both dependent- and independently of PIK3CA mutations, an aspect that should be considered when designing PIK3 pathway targeting strategies in endometrial cancer.

Highlights

Endometrial cancer is the most frequent female pelvic malignancy in industrialized countries and the incidence is increasing[1, 2]
21 of the mutations were found within four amino acids (AAs) located in the helical domain, while 26 mutations were focused at eight AAs in the kinase domain in the primary tumors
As PIK3CA mutations may affect different targets in the PI3K signaling pathway, we investigated these mutations in relation to several molecular markers known to be associated with PI3K pathway activation or to poor prognosis in endometrial cancer (Supplementary Table S5); including protein expression of Stathmin, p85α and phosphatase and tensin homology (PTEN), Kirsten rat sarcoma viral oncogene (KRAS) mutations, PIK3CA amplification

Summary

Introduction

Endometrial cancer is the most frequent female pelvic malignancy in industrialized countries and the incidence is increasing[1, 2]. Recent comprehensive genetic profiling has refined the molecular classification of endometrial carcinomas, reflecting clinical phenotypes[2, 5]. While these differences have prognostic value, they have so far not been utilized therapeutically[4, 6]. P110α is encoded by the PI3K catalytic subunit alpha gene PIK3CA and is the most frequently altered isoform in human cancer[8, 11]. In primary endometrial cancer lesions, PIK3CA is the second most frequently significant mutated gene after PTEN, with a frequency of 53% according to comprehensive genomic profiling including whole exome sequencing performed by The Cancer Genome Atlas (TCGA)[5, 13, 14]. There is conflicting evidence of the effect of PIK3CA mutations on clinical variables in endometrial cancer, relations to depths of myometrial infiltration and differentiation grade have been reported[24, 25]

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