Molecular alterations of EGFR and PTEN in prostate cancer: association with high-grade and advanced-stage carcinomas

Abstract

Prostate cancer is the second cause of cancer-related death in men of the Western world. The potential prognostic role of the combined alterations in EGFR and PTEN in prostate cancer is not well established. It was the aim of the study to investigate this role. Prevalence of EGFR and PTEN somatic mutations, EGFR amplification and EGFR protein expression were investigated in a series of prostate adenocarcinomas, classified according to the current Gleason grading system. Mutational analysis revealed eight EGFR and three PTEN mutations in 98 (8%) and 92 (3%) prostate adenocarcinomas, respectively. The combined prevalence of EGFR-PTEN mutations was 11%. EGFR overexpression was present in 31% of adenocarcinomas, with a marginally significant difference (P ¼ 0.068) between Gleason grade r7 adenocarcinomas and Gleason grade Z8 and metastatic adenocarcinomas. Four cases (4 of 31; 13%) had an EGFR gene gain due to chromosome 7 polysomy. In 35% of adenocarcinomas we found some type of EGFR-PTEN alteration, with a tendency to be associated with advanced-stage prostate adenocarcinomas (P ¼ 0.04). The IVS18 þ 19 polymorphism was also associated with more advanced prostate adenocarcinomas. This is the first study reporting mutations of EGFR and PTEN in the same series of prostate adenocarcinomas. Protein overexpression is the most frequent EGFR abnormality. Mutations in EGFR and PTEN genes are a minor event, although prostate cancer represents the third neoplasm in which the EGFR gene mutations are more prevalent. Alterations in the EGFR-PTEN signaling pathway are present in a third of prostate adenocarcinomas, particularly affecting the more advanced cases. Keywords: EGFR; PTEN; mutation; overexpression; FISH; prostate cancer EGFR belongs to the ErbB family of tyrosine kinase receptors.1 They are activated by binding to peptide growth factors of the EGF family, leading to activation of multiple downstream pathways. The Ras-Raf-MEK-ERK1/2, STAT-3, and STAT-5, and the PI3K/PTEN-Akt-Mtor cascades are the main pathways activated downstream of ErbB receptors, which have strong regulatory effects on cell proliferation, differentiation, survival and migration. 2,3 In many different cancer cell types, the ErbB pathway becomes hyperactivated by a range of mechanisms.2,4

PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications

“…In advanced prostate cancer, both hemizygous and homozygous PTEN deletions have been observed (McMenamin et al, 1999;Verhagen et al, 2006;Schmitz et al, 2007;Liu et al, 2009;Reid et al, 2010), and the incidence of PTEN deletion in castrate-resistant prostate cancer (CRPC) may approach 70-80% (Holcomb et al, 2009;Liu et al, 2009;Sircar et al, 2009;Bismar et al, 2011). Functional loss of PTEN can also be caused by point mutations (Feilotter et al, 1998;Muller et al, 2000;Verhagen et al, 2006;de Muga et al, 2010) or promoter methylation (Whang et al, 1998;Konishi et al, 2002).…”

Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance

“…Phosphatase and tensin homolog (PTEN) is a negative regulator of PI3K/Ak/mTOR pathway (Chang et al, 2014a). PTEN is a highly effective tumor suppressor and frequently mutated, deleted, or epigenetically silenced in various human cancers including CaP (Sircar et al, 2009;de Muga et al, 2010). Due to the important role of the PI3K/Akt/mTOR pathway in cancer research, many valuable inhibitors targeting one signaling node (single inhibitor) or two nodes at the same time (dual inhibitor) in the pathway have been developed in recent years.…”

The biology of castration-resistant prostate cancer

“…Multiple RTK growth factor signaling pathways including EGFR 26,27 , IGF-1R 28,29 , FGFR 30 , PDGFR 31,32 , and HGFR/c-MET 33-35 pathways have been investigated extensively in prostate cancer progression due to their activation of the PI3K-AKT and RAS-MAPK pathways. Combined loss of PTEN with activation of the RAS-MAPK pathway can cooperate to induce epithelial to mesenchymal transition (EMT) and metastases 36 .…”