Pilot investigation of the mutation profile of PIK3CA/PTEN genes (PI3K pathway) in grade 3 endometrial cancer

Abstract

Endometrial cancer (EC) comprises a biological and clinical heterogeneous group of tumors. Several genetic alterations are involved in the development and progression of EC, and may be used for targeted therapy, particularly in patients with advanced-stage EC. In the present study, a combined procedure was developed based on polymerase chain reaction (PCR)-high resolution melting analysis (HRMA) and Sanger sequencing for the evaluation of somatic mutations in selected phosphoinositide 3-kinase (PI3K) catalytic subunit α (PIK3CA; exons 1, 9 and 21) and phosphatase and tensin homolog (PTEN; exons 5, 6, 7 and 8) exons. This combined procedure has the specificity and sensitivity of the two techniques, and overcomes their limitations. A pilot study was performed on 18 selected homogenous EC samples, of grade 3 endometrioid subtype (G3 EEC). First, the feasibility of the combined procedure was investigated to properly identify the presence of somatic mutations on PIK3CA and PTEN, the variations identified were analyzed using Catalogue of Somatic Mutations in Cancer, PolyPhen-2 and Mutation Taster software, and the frequency of mutations/variations was determined in the selected samples. The evaluation of mutational load revealed that the majority of the G3 EEC samples exhibited PIK3CA mutations (39%) and PTEN mutations (67%), and the majority of the samples (83%) had mutations in at least one of the two genes, and 33% had mutations in the two genes. The results of the present pilot study suggested that the cost-effective combined PCR-HRMA and Sanger sequencing procedure may be suitable for identification of PTEN and PIK3CA mutations in G3 EEC and that their frequency was consistent in G3 EEC, indicating that the PI3K pathway serves a pivotal function that may have potential for defining targeted therapy for the treatment of G3 EEC.

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Hereby, the remarkable overall genetic alterations of PI3K/AKT pathway are shown in EC, such as: PIK3CA (34%), PIK3R1 (19%), PIK3R2 (5%), AKT1 (3%) and AKT2 (5%), especially PTEN (32%, Table 1). What's more, it's revealed that the majority of the G3 EEC samples have exhibited PIK3CA mutations (39%) and PTEN mutations (67%) [227]. Moreover, JQ1, NEDD4, PDCD4, miR-101, -494-3p, Lnc RNA LINP1 and MEG3 have shown their aptitudes for controlling tumorigenesis, proliferation, apoptosis, invasion, progression of EC cells via PI3K/AKT pathway [228][229][230][231][232][233][234].…”

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

“…PIK3CA mutations have been reported in urothelial papilloma cases [111]. PIK3CA gene amplification has been observed in recurrent ovarian cancer [112] and yolk sac tumors [113]. In addition, PIK3CA mutation was identified in 38% endometrial cancer samples [114].…”

Alteration of tumor associated neutrophils by PIK3CA expression in endometrial carcinoma from TCGA data

“…UCSC disrupts a lot of signal pathways including PI3K/PTEN/AKT/mTOR pathway [3]. PI3K pathway serves a pivotal function that may have potential for defining targeted therapy for the treatment of grade 3 UCEC [4]. The main component of PI3K pathway, PIK3CA, is a strong prognostic biomarker in UCEC and associates with disease-specific mortality [5].…”