Genetic variants of the EGFR ligand-binding domain and their association with structural alterations in Arab cancer patients

Abstract Objective This study aimed to identify novel genetic variants in the CR2 extracellular domain of the epidermal growth factor receptor (EGFR) in healthy individuals and patients with six different types of adenocarcinoma, in Arabian peninsula populations. It also aimed to investigate the effects of these variants on the EGFR structure and their eventual relevance to tumorigenesis. Results We detected seven new EGFR genetic variants in 168 cancer patients and 114 controls. A SNP rs374670788 was more frequent in bladder cancer but not significantly associated to. However, a missense mutation (V550M) was significantly associated to colon, ovary, lung, bladder and thyroid cancer samples (p < 0.05). Three mutations (H590R, E602K and T605T) were found in the heterozygous form only in colon cancer patients. Genomic analysis of the synonymous mutation (G632G) showed that the T/A genotype could be associated to thyroid cancer in Arab patients (p < 0.05). An additional novel SNP rs571064657 was observed in control individuals. Computational analysis of the genetic variants revealed a reduction in the stabilization of the EGFR tethered form for both V550M and the common R521K variant with low energetic state (− ∆∆G). Molecular interactions analysis suggested that these mutations might affect the receptor’s function and promote tumorigenesis.

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In Silico Drug Prescription for Targeting Cancer Patient Heterogeneity and Prediction of Clinical Outcome

Cancers ◽

10.3390/cancers11091361 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1361

Author(s):

Elena Piñeiro-Yáñez ◽

María José Jiménez-Santos ◽

Gonzalo Gómez-López ◽

Fátima Al-Shahrour

Keyword(s):

Cancer Patients ◽

In Silico ◽

Tumour Progression ◽

Drug Prescription ◽

A Priori ◽

Growth Factor Receptor ◽

Clonal Diversity ◽

Molecular Alterations ◽

Patient Heterogeneity ◽

Epidermal Growth

In silico drug prescription tools for precision cancer medicine can match molecular alterations with tailored candidate treatments. These methodologies require large and well-annotated datasets to systematically evaluate their performance, but this is currently constrained by the lack of complete patient clinicopathological data. Moreover, in silico drug prescription performance could be improved by integrating additional tumour information layers like intra-tumour heterogeneity (ITH) which has been related to drug response and tumour progression. PanDrugs is an in silico drug prescription method which prioritizes anticancer drugs combining both biological and clinical evidence. We have systematically evaluated PanDrugs in the Genomic Data Commons repository (GDC). Our results showed that PanDrugs is able to establish an a priori stratification of cancer patients treated with Epidermal Growth Factor Receptor (EGFR) inhibitors. Patients labelled as responders according to PanDrugs predictions showed a significantly increased overall survival (OS) compared to non-responders. PanDrugs was also able to suggest alternative tailored treatments for non-responder patients. Additionally, PanDrugs usefulness was assessed considering spatial and temporal ITH in cancer patients and showed that ITH can be approached therapeutically proposing drugs or combinations potentially capable of targeting the clonal diversity. In summary, this study is a proof of concept where PanDrugs predictions have been correlated to OS and can be useful to manage ITH in patients while increasing therapeutic options and demonstrating its clinical utility.

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Increased serum level of epidermal growth factor receptor in liver cancer patients and its association with exposure to arsenic

The Science of The Total Environment ◽

10.1016/j.scitotenv.2012.02.079 ◽

2012 ◽

Vol 424 ◽

pp. 74-78 ◽

Cited By ~ 9

Author(s):

Tzu-I Sung ◽

Ying-Jan Wang ◽

Chi-Yi Chen ◽

Tsui-Lien Hung ◽

How-Ran Guo

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Serum Level ◽

Liver Cancer ◽

Cancer Patients ◽

Growth Factor Receptor ◽

Epidermal Growth

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Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A

Endocrine Related Cancer ◽

10.1677/erc.1.01226 ◽

2006 ◽

Vol 13 (4) ◽

pp. 1173-1183 ◽

Cited By ~ 45

Author(s):

Michael W Yeh ◽

Jean-Philippe Rougier ◽

Jin-Woo Park ◽

Quan-Yang Duh ◽

Mariwil Wong ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Thyroid Cancer ◽

Growth Factor ◽

Cell Lines ◽

Cancer Cell ◽

Cell Invasion ◽

Growth Factor Receptor ◽

Thyroid Cancer Cell ◽

Cancer Cell Invasion ◽

Epidermal Growth

Mechanisms of invasion in thyroid cancer remain poorly understood. We hypothesized that signaling via the epidermal growth factor receptor (EGFR) stimulates thyroid cancer cell invasion by altering the expression and cleavage of matrix metalloproteinases (MMPs). Papillary and follicular carcinoma cell lines were treated with EGF, the EGFR tyrosine kinase inhibitor AG1478, and the MMP inhibitors GM-6001 and Col-3. Flow cytometry was used to detect EGFR. In vitro invasion assays, gelatin zymography, and quantitative reverse transcription-PCR were used to assess the changes in invasive behavior and MMP expression and activation. All cell lines were found to overexpress functional EGFR. EGF stimulated invasion by thyroid cancer cells up to sevenfold (P < 0.0001), a process that was antagonized completely by AG1478 and Col-3, partially by GM-6001, but not by the serine protease inhibitor aprotinin. EGF upregulated expression of MMP-9 (2.64- to 8.89-fold, P < 0.0001) and membrane type-1 MMP (MT1-MMP, 1.97- to 2.67-fold, P < 0.0001). This effect was blocked completely by AG1478 and partially by Col-3. The activation of MMP-2 paralleled MT1-MMP expression. We demonstrate that MMPs are critical effectors of invasion in the papillary and follicular thyroid cancer cell lines studied. Invasion is regulated by signaling through EGFR, an effect mediated by augmentation of gelatinase expression and activation. MMP inhibitors and growth factor antagonists may be effective tumoristatic agents for the treatment of aggressive thyroid carcinomas.

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