Exon 9 Mutation of PIK3CA Associated With Poor Survival in Patients With Epstein-Barr Virus-associated Gastric Cancer

Abstract

Background: Epstein-Barr virus (EBV)-associated gastric cancer (GC) is known to harbor a significant enrichment of of phosphatidylinositol 4, 5-biphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA). Therefore, this study investigated the clinical relevance and prognostic role of PIK3CA mutations in patients with EBV-GC. Materials and Methods: After reviewing 1,318 consecutive cases of surgically resected GC, 120 patients were identified as EBV-positive using EBV-encoded RNA in situ hybridization. PIK3CA mutations were identified in formalin-fixed and paraffin-embedded surgical specimens from 112 patients with EBV-GC with available tumor tissue samples. Real-time polymerase chain reaction was used to evaluate hot-spot mutations of exons 1, 4, 7, 9, and 20 of PIK3CA. Results: Among the 112 patients, the frequency of PIK3CA mutations was 25.0% (n=28), and among the 28 patients harboring a PIK3CA mutation, most mutations were identified in exon 9 (n=21, 18.8%). The presence of PIK3CA mutation was also correlated with a higher T category (p<0.001) and N category (p<0.001), as well as the presence of perinueral invasion (p<0.001) and venous invasion (p<0.001). In a univariate analysis, PIK3CA mutation showed no association with overall survival (OS) (p=0.184) or disease-free survival (DFS) (p=0.150). Patients harboring exon 9 PIK3CA mutations exhibited a significantly shorter OS (p=0.023) and DFS (p=0.013) than the patients lacking an exon 9 PIK3CA mutation, yet without statistical significance in the multivariate analysis. Notably, exon 9 E542K mutation of PIK3CA was associated with the worst DFS (p=0.011). Conclusion: The current data show that PIK3CA mutations appear to play an important role in carcinogenesis and tumor aggressiveness in EBV-GC, and also support the concept that exon 9 mutation of PIK3CA is a prognostic indicator for predicting patient outcomes and a rationale for therapeutic targeting in EBV-GC.The Cancer Genome Atlas (TCGA) research group identified four genomic subtypes of gastric cancer (GC): Epstein-Barr 2145

The Clinicopathological Features and Genetic Alterations in Epstein–Barr Virus-Associated Gastric Cancer Patients after Curative Surgery

“…An interesting finding that the incidence of PI3K/AKT pathway mutation was 25.9% (11/43) in EBV-positive GC patients in the present study, which was similar to findings in a Korean study [22] (25%, 28/112) and significantly lower than that in The Cancer Genome Atlas (TCGA) database (80%, 21/26). The discrepancy might be due to racial differences and the relatively small patient number of EBV-positive tumors in all three studies.…”

Case Report: Analysis of Circulating Tumor Cells in a Triple Negative Spindle-Cell Metaplastic Breast Cancer Patient

“…Investigation of the primary tumor performed through an NGS-based approach detected alterations that are not uniquely ascribable to MpBC and failed to underline effective actionable targets to address the therapeutic strategy. Indeed, MYC copy number gain ( 13 , 14 ) and PIK3CA mutation ( 15 , 16 ) are widely described in the literature to be involved in many cancer types, including BC ( 17 , 18 ). Herein, by exploiting a liquid biopsy approach, we emphasize that the characterization of CTCs, rare cells with a crucial role in the metastatic cascade, could be worthwhile to guide the investigation of the molecular mechanisms underlying rare tumors.…”

Overview of Epstein–Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options

“…Mutations in exons 9 and 20 in PI3K catalytic subunit alpha (PIK3CA) as well as mutations in phosphatase and tensin homolog (PTEN), AKT1, AKT2, and AKT3 lead to deregulation of the PI3K-Akt-mTOR pathway; they have been proposed as biomarkers to test novel compounds and dosing schedules [145]. They are also associated with peritoneal recurrences [145][146][147], resulting in AKT and PTEN having immunohistochemistry prognostic value for patient survival [148]. Circular RNA AKT3 (circ AKT3) was found to be associated with PIK3/Akt activation in GC and resistance to cisplatin [149][150][151].…”