EGFR gene deregulation mechanisms in lung adenocarcinoma: A molecular review

For the last two decades, evolution in molecular biology has expanded our knowledge in decoding a broad spectrum of genomic imbalances that progressively lead normal cells to a neoplastic state and finally to complete malignant transformation. Concerning oncogenes and signaling transduction pathways mediated by them, identification of specific gene alterations remains a critical process for handling patients by applying targeted therapeutic regimens. The epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in regulating cell proliferation, differentiation and apoptosis in normal cells. EGFR mutations and amplification represent the gene's main deregulation mechanisms in cancers of different histo-genetic origin. Furthermore, intra-cancer molecular heterogeneity due to clonal rise and expansion mainly explains the variable resistance to novel anti-EGFR monoclonal antibody (mAb), and also tyrosine kinase inhibitors (TKIs). According to recently published 2015 WHO new classification, lung cancer is the leading cause of death related to cancer and its incidence is still on the increase worldwide. The majority of patients suffering from lung cancer are diagnosed with epithelial tumors (adenocarcinoma predominantly and squamous cell carcinoma represent ∼85% of all pathologically defined lung cancer cases). In those patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify patients’ sensitivity (i.e. exon 21 L858R, exon 19 LREA deletion) or resistance (ie exon 20 T790 M and/or insertion) to TKI mediated targeted therapeutic strategies. Additionally, the role of specific micro-RNAs that affect EGFR regulation is under investigation. In the current review, we focused on EGFR gene/protein structural and functional aspects and the corresponding alterations that occur mainly in lung adenocarcinoma to critically modify its molecular landscape. © 2016 Elsevier Gmb

Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis

Estrogen receptor alpha-encoded by ESR1 gene-overexpression correlates with prognosis and response to specific chemotherapy in breast adenocarcinoma cases. Mechanisms of ESR-1 deregulation in carcinomas remain under investigation. To analyze ESR1 in carcinomas of different histogenesis. Using tissue microarray technology, 172 primary carcinomas including breast ductal adenocarcinomas (n = 60), hepatocellular carcinomas (n = 52), and colon adenocarcinomas (n = 60) were cored and re-embedded in three paraffin blocks. Initial diagnosis was based on liquid based cytology (LiquiPrep/ThinPrep). Immunohistochemistry and fluorescence in situ hybridization were performed. Quantitative evaluation of ER-a protein levels was assessed by applying digital image analysis. ER-a overexpression was observed in 41/60 (68.3%), 23/52 (44.2%) and 4/60 (6.6%) cases, respectively. ESR1 gene multiple copies were confirmed in 13/60 (21.6%) breast adenocarcinomas, but high amplification only in 8/13 (62.8%). Allelic absence was identified in 3/52 (5.7%) hepatocellular carcinomas, whereas colon adenocarcinomas demonstrated gene gains in 5/60 (8.3%) cases referred to chr 6 aneuploidy and not to amplification. ER-a overall expression was associated strongly to ESR1 gene copies only in breast carcinoma (P = 0.036). ESR-1 gene overexpression happens frequently in breast cancer, but only a subset of them are high amplified cases correlated to increased response rates in hormonal therapy (tamoxifen). Absence of this mechanism in hepatocellular and colon carcinomas maybe is a negative factor for applying this therapy. This is a pattern of histo-genetic depended targeted therapeutic strategy. © 2010 Springer Science+Business Media, LLC

Chromosome 7 multiplication in EGFR-positive lung carcinomas based on tissue microarray analysis

Background/Aim: Epidermal growth factor receptor (EGFR) over-activation is observed in significant proportions of non-small cell lung carcinomas (NSCLC). Our aim was to investigate the role of chromosome 7 multiplication with regard to its influence in EGFR expression, combined or not with gene amplification. Materials and Methods: Using tissue microarray technology, fifty (n=50) primary NSCLCs were cored and re-embedded into the final recipient block. Immunohistochemistry (IHC) and also chromogenic in situ hybridization (CISH) were performed. Results: EGFR expression at any level was detected in 40/50 (80%) cores. Over-expression was observed in 23/40 (57.5%) cases. Gene amplification was identified in 11/50 (22%) cases whereas chromosome 7 polysomy in 8/50 (16%) cases. Pure chromosome 7 multiplication alone led to low or moderate levels of expression. Overall EGFR expression was correlated with gene (p=0.001) and interestingly with chromosome 7 centromere numerical imbalances (p=0.004). Conclusion: EGFR expression is associated not only with amplification, but also with chromosome 7 centromere multiple copies. Chromosome 7 multiplication -due to centromere region amplification or true polysomy- is critical for applying monoclonal antibody targeted therapeutic strategies excluding the pure non-amplified cases