Epidermal growth factor receptor (EGFR) is a cell-membrane receptor tyrosine kinase belonging to the EGF-family of receptors, which binds a variety of extracellular protein ligands, including epidermal growth factor and transforming growth factor-alpha. Upon ligand-binding, two monomeric EGFR molecules bind together to form a homodimer, which gets activated by autophosphorylation. Following activation, the receptor dimer complex proceeds to phosphorylate cytoplasmic substrates, initiating a signaling cascade that drives many cellular responses, including changes in gene expression, cytoskeletal rearrangement, anti-apoptosis, and increased cell proliferation. Incidentally, EGFR can also pair with any other member of the EGF-family of receptors to form a heterodimer.
Due to its central role in processes such as cell division, mutations in the EGFR gene that result in a constitutive production of the protein tend to cause uncontrolled cell proliferation. EGFR mutations have been associated with different types of cancers, most notably epithelial cancers. About 30% of human primary tumors show an over-expression of EGFR, and this over-expression has also been significantly associated with disease stage, prognosis, survival, and response to chemotherapy. Of late, EGFR has been recognized as a suitable target for cancer therapy.
EGFR gene is located on chromosome 7 and it has several alternatively spliced transcripts, which encode different protein isoforms. The main isoform, isoform A, is encoded by two different transcripts of 10.5 Kb and 5.8 Kb. Isoform A consists of 1210 amino acids, and measures 135 kDa. Additionally, there exist at least three other alternate transcripts of 1.8, 2.4, and 3.0 Kb that encode for isoforms C, B, and D, respectively.
Several mutations in the EGFR gene have been implicated in different types of carcinomas. In the case of non-small cell lung cancer, a large majority of patients have been shown to carry EGFR mutations within a hotspot region between exons 18 and 21, which encodes the kinase domain.
Nasralla et al. (1992) studied the relation between epidermal growth factor levels and estrogen and progesterone receptors in 132 primary breast cancer tissue specimens. An inverse significant correlation was observed between ER and PR levels vs. epidermal growth factor receptor levels in tumors of post-menopausal women. No such correlation could be seen in pre-menopausal patients. While EGFR positive tumors showed no significant difference in the levels of ER and PR in premenopausal and postmenopausal women, EGFR negative tumors showed a significantly higher value in the postmenopausal women.
Kharrat et al. (2007) genotyped 252 healthy individuals and 118 female breast cancer patients from Kuwait and Tunisia for the polymorphic AC repeat in intron 1 of the EGFR gene. Both the Kuwaiti and Tunisian populations were found to be very similar to each other in terms of allelic and genotypic frequencies in both control and patient groups. However, when the results were compared to those reported from other populations, several interethnic differences could be noted. The most frequent allele noted in this study was allele 17, while in Europeans and Asians, it was allele 16 and 20, respectively. Comparing the breast cancer cases to 123 healthy women, a strong association was found for allele 18 with susceptibility to breast cancer. This also contrasted with reports from Asian populations, where allele 16 was identified as the risk allele.
El Hamdani et al. (2010) evaluated the frequency of point mutations in the EGFR gene to assess the potential use of tyrosine kinase inhibitors in clinical treatment and the use of EGFR, p16INK4a and E-cadherin as biomarkers in cervical cancer diagnosis with immunohistochemistry. Of 53 patient specimens of cervical cancer, 79% (42/53) were HPV positive and the HPV types more closely associated with risk were HPV 16 and 18. In all specimens, no mutation affecting the EGFR kinase domain in exons 18 through 21 was observed. Expressions of EGFR, p16INK4a and E-cadherin were detected in 89% (47/53), 92% (49/53) and 79% (42/53) of all specimens respectively. El Hamdani et al. (2010) concluded that treatment of cervical cancer with TKIs may not be effective and that the identification of other EGFR inhibitors is yet needed.
Naji et al. (2010) studied 60 specimens of nasopharyngeal carcinoma (NPC) to assess the presence of EGFR mutations in exons 18 and 21. Again, there no mutations detected in the EGFR kinase domain in these exons in all samples analyzed. Sequence analysis of the EGFR-TK domain, revealed the presence of a G2607A polymorphism at exon 20. The genotypes AA and GA were found, respectively, in 39 (65%) and 16 (26.6%) cases. Statistical analysis showed no difference between the polymorphism and either gender or age of patients.
[See: Kuwait > Kharrat et al., 2007].