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The Oncologist, Vol. 12, No. 2, 201-210, February 2007; doi:10.1634/theoncologist.12-2-201
© 2007 AlphaMed Press

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Lung Cancer

Genetic Polymorphisms of the Epidermal Growth Factor and Related Receptor in Non-Small Cell Lung Cancer—A Review of the Literature

António Araújoa,b,c, Ricardo Ribeirob,c, Isabel Azevedoa, Ana Coelhoc, Marta Soaresa, Berta Sousaa, Daniela Pintoc, Carlos Lopesb,c, Rui Medeirosb,c, Giorgio V. Scagliottid

a Department of Medical Oncology, Portuguese Institute of Oncology, Porto Centre, Porto, Portugal b ICBAS, Abel Salazar Institute for Biomedical Sciences, University of Porto, Porto, Portugal c Molecular Oncology—CI, Portuguese Institute of Oncology, Porto Centre, Porto, Portugal d Department of Clinical and Biological Sciences, University of Torino, Torino, Italy

Key Words. Epidermal growth factor • Epidermal growth factor receptor • Polymorphism • Non-small cell lung cancer

Correspondence: António Araújo, M.D., Department of Medical Oncology, Portuguese Institute of Oncology, Porto Centre, Rua Dr. António Bernardino de Almeida, 4200 Porto, Portugal. Telephone: 00351-22-5084000; Fax.: 00351-22-5084008; e-mail: amfaraujo{at}netcabo.pt

Received August 3, 2006; accepted for publication November 6, 2006.


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Conclusion
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the role played by EGF and EGFR in lung carcinogenesis.
  2. Discuss how different polymorphic alleles from the EGF and EGFR genes may affect drug response.
  3. Evaluate the value of determining the presence of EGF and EGFR polymorphisms in NSCLC patients for daily clinical practice.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Conclusion
 Disclosure of Potential...
 References
 
Worldwide, approximately 1.3 billion individuals are current smokers, and smoking is the second major cause of death. Currently, lung cancer is the most common type of cancer in Europe, and the third in the U.S. Until now, cytotoxic chemotherapy has had a limited impact on survival in metastatic non-small cell lung cancer (NSCLC). The central role of epidermal growth factor (EGF) and its receptor (EGFR) in lung carcinogenesis is well recognized. Genetic polymorphisms are variants in individual genomes that may be responsible for different functional molecular roles and contribute to variability in drug pharmacokinetic and pharmacodynamic processes. Herein, we review the literature on EGF and EGFR functions and activities, particularly the current role of their functional polymorphisms as related to NSCLC.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Conclusion
 Disclosure of Potential...
 References
 
In 2005, it was estimated that 11 million people were diagnosed with cancer worldwide. Currently, lung cancer is the most common type of cancer in Europe (381,500 new cases in 2004) [1] and the third in the U.S. (172,570 new cases in 2005) [2]. During 2004, 341,800 deaths were attributable to lung cancer in Europe [1], whereas corresponding data in the U.S. for 2005 indicate 163,510 deaths [2].

Trends of cigarette smoking consumption in each country nicely predict the respective lung cancer incidence, with a gap of almost 20 years between the two curves. Furthermore, it is well known that lung cancer incidence and mortality rates are quite superimposed, making lung cancer the most common cause of cancer-related death in North America and Europe today [1]. Currently, tobacco smoking represents a less common cause of death in developing continents, such as Africa and Eastern Asia [3], where competing causes of death remain present. It has been estimated, however, based on current trends of cigarette consumption in countries such as India and China, that lung cancer will become a relevant social disease in those areas of the world in the next 20 years [4] (Fig. 1Go).


Figure 1
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  		Figure 1. A descriptive model of the cigarette epidemic. From Lopez AD, Collishaw NE, Piha T. A descriptive model of the cigarette epidemic in developed countries. Tobacco Control 1994;3:242–247. Reproduced with permission from the BMJ Publishing Group.

 
Non-small cell lung cancer (NSCLC) accounts for 75%–85% of all histotypes of lung cancer. Despite extensive preclinical and clinical research, the overall prognosis for patients with NSCLC remains poor, with a 5-year survival rate of only 14% [5]. Surgery remains the most effective therapeutic modality with curative intent in early-stage NSCLC, but postoperative survival remains unsatisfactory, with a 5-year survival rate less than 70% even in pathologic stage I disease [6]. Consequently, more than 70% of NSCLC patients are candidates for neoadjuvant, adjuvant, or palliative systemic treatment with chemotherapy (CT) at some point in their disease progression. Although patients with metastatic NSCLC clearly benefit from cytotoxic CT, the current limited impact on survival with an average prolongation of survival of no more than 2 months should also be recognized [7].

Proliferative activity of cancer cells may be maintained through several mechanisms, including autocrine loops; consequently, cancer cells exhibit a reduced requirement for exogenously supplied growth factors [8]. This independence from external supply is, at least partially, secondary to the ability of cancer cells to produce high levels of their own peptide growth factors, and this depends, in turn, on the activation of cellular proto-oncogenes [9, 10]. Similarly, the involvement of growth factors in sustaining the survival of cancer cells and in promoting tumor-induced neoangiogenesis has been definitively established, contributing to tumor progression through different mechanisms.

In recent years, knowledge concerning the molecular mechanisms underlying cellular transformation and development of cancer has been greatly expanded. Therefore, new therapeutic agents, driven to specific intra- or extracellular targets, presumed to be crucial in the molecular pathways of carcinogenesis, have been developed. Among the different families of growth factors and growth factor receptors, the epidermal growth factor (EGF) and its receptor (EGFR) play a central role in lung carcinogenesis. Following stimulation by its ligands, EGFR initiates signal transduction cascades, which promote proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis [11] (Fig. 2Go). In the late 1990s, EGFR was discovered to play an important role in tumoral biology and to be an attractive therapeutic target. Therefore, different therapeutic strategies capable of interfering with the EGFR pathway activation were developed. Examples of these are different types (e.g., murine, chimeric, and humanized) of monoclonal antibodies (mAbs), which bind to the extracellular domain of the receptor and compete with the natural ligands (transforming growth factor {alpha} [TGF-{alpha}] and EGF), some of them currently in clinical trial (e.g., cetuximab, matuzumab, and panitumumab). mAbs interact with receptor dimerization, resulting in receptor downregulation that may be important for their growth-inhibitory capacity [12]. Another class of agents, the low molecular weight tyrosine kinase inhibitors (TKIs; e.g., gefitinib and erlotinib), compete with ATP binding to the TK portion of the intracellular domain of the receptor and abrogate the receptor’s catalytic activity. These therapeutic strategies seem to be both equally effective in blocking the downstream receptor-dependent signaling pathways, including the phosphatidylinositol 3-kinase/Akt, the janus kinase/signal transducer and activator of transcription, and the mitogen-activated protein kinase pathways [11]. In 2003, gefitinib [13], one of the EGFR-TKIs, was conditionally approved by the U.S. Food and Drug Administration for the treatment of CT-refractory locally advanced or metastatic NSCLC, based on clinical benefit data. More recently, another EGFR-TKI agent, erlotinib, has been approved in the U.S. and Europe for second- and third-line treatment of NSCLC because of a superiority over best supportive care as demonstrated by a phase III clinical study [14].


Figure 2
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  		Figure 2. Epidermal growth factor receptor signal transduction pathways. From Tabernero J, Macarulla T, Ramos FJ et al. Novel targeted therapies in the treatment of gastric and esophageal cancer. Ann Oncol 2005;16:1740–1748.[Abstract/Free Full Text] Reprinted with permission from Oxford University Press.

Abbreviations: FKHR, forkhead-winged helix protein; GSK-3, glycogen synthase kinase-3; Grb2, growth-factor receptor-bound protein 2; MAPK, mitogen-activated protein kinase; MEK1/2, MEK, mitogen-activated protein kinase kinase 1/2; NF-{kappa}B, nuclear factor-{kappa}B; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PT, phospho-threonine; Raf, serine kinase Raf; Ras, GTP-binding protein Ras; Shc, Src homologous and collagen protein; Sos, guanine nucleotide exchange factor Sos.

 
Pharmacogenetics and pharmacogenomics are emerging areas that will be crucial for personalized medicine, ultimately leading to drug prescription based on a patient’s individual genetic and molecular profile [15]. Their aim is to establish a meaningful relationship between genotype (i.e., polymorphisms and genetic mutations), gene expression profiles (i.e., level of gene expression of all or of target genes in the genome), and phenotype, interpreted as the variability among individuals in terms of response and toxicity to different drugs. Pharmacogenetics commonly refers to the effects that involve a limited number of genes, often connected to drug metabolism, whereas pharmacogenomics involves the study of complex multigene patterns within the genome. Genetic polymorphisms are variants in individual genomes, present in more than 1.5% of the population, that remain constant throughout a person’s lifetime [15]. There are more than 1.4 million single nucleotide polymorphisms (SNPs) identified in the human genome, and many of them contribute to variability in both pharmacokinetic and pharmacodynamic drugs [16]. Genetic mutations are acquired changes in gene sequences and occur only in certain cells. The interindividual genetic variation may also be an important factor in the characterization of susceptibility for the development of cancer and of variability to drug response [17–23].

In the context of molecular epidemiology and pharmacogenomic investigation, it is also important to remember that prognostic factors are patient and tumor characteristics that predict patients’ outcome (usually survival) and are independent from the type of administered treatment. Predictive factors are clinical, cellular, and molecular markers that predict response of the tumor to treatment (either in terms of tumor shrinkage or a survival benefit from treatment). Thus, prognostic factors define the effects of tumor characteristics on the patient, whereas predictive factors define the effect of treatment on the tumor [24].

EGFR
EGFR is a transmembranal glycoprotein encoded by a gene located in the short arm of chromosome 7 (chromosome 7p12.1–12.3). It has an Mr of 170,000 (1186 amino acids) [25] and contains 26 exons [26]. Exons 1–14 code the extracellular domain, exon 15 codes the transmembrane region, and exons 16–20 code the intracellular domain. This receptor belongs to the ErbB family of TK receptors, whose other members include ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) [27, 28]. Structurally, each protein of this family has an extracellular ligand-binding domain, a transmembrane hydrophobic domain, and an intracellular TK-containing domain. Except for ErbB3, they all have intrinsic TK activity [29]. The receptors exist as inactive monomers, and ligand binding causes dimerization, autophosphorylation of the adjacent intracytoplasmic domains (trans-autophosphorylation), and activation of the intracellular TK activity. This reaction is accompanied by recruitment of downstream signal transduction molecules, leading to activation of different pathways [30], and to effects in genetic expression, cellular proliferation, inhibition of apoptosis, and angiogenesis [31]. During carcinogenesis, the signaling system is frequently deregulated, and overexpression of EGFR is associated with aggressiveness, worse clinical prognosis, and chemo- and radioresistance in a variety of tumors [32–34].

The initial ErbB receptor-ligand and receptor-receptor interaction occurs on the cellular surface. ErbB receptors are activated by binding to growth factors of the EGF family, which are characterized by the presence of an EGF-like domain composed of three disulfide-bonded intramolecular groups that confer binding specificity, and additional structural areas such as immunoglobulin-like domains, heparin-binding sites, and glycosylation sites. These EGF-related growth factors, including amphiregulin and TGF-{alpha}, can specifically bind to EGFR. They can show dual specificity for EGFR and ErbB-4, such as the betacellulin, epiregulin, and heparin-binding EGF. The third group is composed of the neuregulins (NRGs), divided into two subgroups based on their capacity to bind ErbB-3 and ErbB-4 (NRG-1 and NRG-2) or only ErbB-4 (NRG-3 and NRG-4) [35–38]. None of the EGF-family peptides binds directly ErbB-2.

This interaction induces the ErbB receptor to dimerization, which may occur between two receptors of the same family (heterodimerization; i.e., ErbB1-ErbB3) or between identical receptors (homodimerization; i.e., ErbB1-ErbB1). Stimulation by a specific ligand confers a unique dimerization profile that is also tissue- or tumor-specific [28]. The dimerization process leads to activation of the TK domain of the receptor and is followed by phosphorylation of multiple tyrosine residues, activating downstream proteins, and finally originating physiologic responses [28, 39].

Homodimers of EGFR signal weakly, in part due to receptor downregulation and degradation after ligand-mediated activation. The EGFR homologous HER2 receptor, which is highly expressed in several human cancers, can potentiate EGFR function by increasing EGF binding affinity, stabilizing and recycling EGFR-HER2 heterodimers, and expanding the repertoire of receptor-associated substrates and signaling responses [40, 41] (Fig. 3Go). In addition, the dimer degradation, initiated by ligand binding, induces receptors to cluster in clathrin-coated membrane pits, which is followed by endocytosis and eventual lysosomal degradation of the dimer [42]. However, in the kinase-negative mutants, recycling to the cell surface for reutilization is observed, and therefore, dimers are not degraded as much [43].


Figure 3
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  		Figure 3. The erbB receptor dimerization, the epidermal growth factor receptor (EGFR) downstream signaling pathway, and the tyrosine kinase (TK) inhibitor’s influence in cell outcome. Abbreviations: AR, amphiregulin; EPR, epiregulin; GRB2, growth-factor receptor-bound protein 2; HB-EGF, heparin-binding epidermal growth factor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; NRG, neuregulin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLC-{gamma}, phospholipase C {gamma}; RAF, serine kinase Raf; RAS, GTP-binding protein Ras; SOS, guanine nucleotide exchange factor Sos; STAT, signal transducer and activator of transcription; TGF-{alpha}, transforming growth factor {alpha}.

 
EGFR may crosstalk with heterologous receptors activated by neurotransmitters, lymphokines, and stress inducers. G-protein-coupled receptors can exert positive effects on EGFR signaling in several ways, including the activation of matrix metalloproteinases, which cleave membrane-bound EGFR ligands that can bind and activate EGFR [27].

Inhibition of EGFR Pathway by Low-Weight TKIs
EGFR is expressed in a variety of solid tumors, including NSCLC, cancer of the head and neck, and colorectal cancer. Overexpression of EGFR is found in 43%–83% of NSCLC, and it is more likely to occur in squamous cell carcinoma (70%), followed by adenocarcinoma (50%) and, to a lesser extent, in large-cell carcinoma [30]. It is a rare phenomenon in small-cell lung cancer.

Several phase II and phase III studies in second- and third-line treatment of NSCLC, in which gefitinib and erlotinib have been investigated as monotherapy, showed response rates ranging from 5% to 15% in different tumor types [14, 44, 45]. Since the time of pivotal phase II studies with gefitinib, a higher level of activity in selected subgroup of patients was clearly noted, including nonsmokers, Asian ethnicity, women, and patients with a diagnosis of adenocarcinoma. More recently, it was found that patients with NSCLC harboring somatic mutations in the TK domain receptor (the most common type is a short in-frame deletion of 9, 12, 15, 18, or 24 nucleotides in exon 19 or a point mutation, CTG to CGG, in exon 21 that results in substitution of leucine by arginine at codon 858, L858R) were extremely sensitive to EGFR inhibitors and obtained substantial and prolonged responses [46, 47]. There is also growing evidence suggesting that EGFR mutations are favorable prognostic markers of survival and that they are predictive markers of response in terms of tumor shrinkage. However, until now, there has been no evidence that suggests that they are predictive of a differential effect of EGFR inhibitor therapy on survival [24]. Other authors showed that the determination of EGFR gene copy numbers—by polymerase chain reaction or by fluorescence in situ hybridization (FISH)— could be a valuable tool in identifying a population of patients with NSCLC that will have a better response to EGFR-TKIs, time-to-progression, and an improved overall survival rate [48, 49]. At present, it is still unknown whether the determination of EGFR mutations in the TK domain by DNA sequencing, the number of copies of its gene by FISH, the determination of EGFR protein expression by immunohistochemistry, or a combination of these methods should be used in helping to predict which patients will benefit more from treatment with EGFR-directed drugs [50].

EGFR Polymorphisms
It is well known that interethnic differences are frequently observed in the distribution of polymorphisms in the drug-metabolizing enzymes, targets, receptors, and transporters. These may justify the interindividual variation in the response to the drugs and the obtained toxicity [51]. Overexpression of EGFR has been linked to amplifications of the EGFR gene located at 7p13-12. In most tumors, and especially in breast cancer, the main reason for overexpression has to be viewed at the gene transcription level.

In EGFR, the regulatory sequences of the gene have been demonstrated within the 5'-flanking region and intron 1 [52]. Two sequences with enhancer activity were located upstream in the promoter and downstream in intron 1. In this specific intron of EGFR, a highly polymorphic (CA)n repeat was identified [53] (Fig. 4Go). Eight alleles with 14–21 (CA)n repeats were found. Allele 16 (alleles are designated according to the number of repeats) showed the highest frequency (42%), followed by allele 20 (26%), allele 18 (20%), and allele 25 (5%). The other alleles are relatively rare [51].


Figure 4
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  		Figure 4. 5'-region of the EGFR gene (adapted from Gebhardt et al [59]). Abbreviation: EGFR, epidermal growth factor receptor.

 
Recent in vitro and in vivo studies showed that transcriptional activity of EGFR is reduced with more CA repeats [53] (Fig. 5Go). The longer allele 21 induced an 80% reduction in the gene expression compared with the shorter allele 16 [54, 55]. Thus, the length of this (CA)n dinucleotide polymorphism is inversely related to the transcriptional activity of the gene. In addition, a constant decline of intratumoral EGFR protein expression was also observed to be associated with an increase in allele length [55].


Figure 5
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  		Figure 5. Relative transcription activity of the 5'-region of the EGFR gene in vitro (adapted from Gebhardt et al [59]).

 
Given the association between the expression of the gene and the polymorphic (CA)n repeat, the response to therapy with EGFR inhibitors may vary among patients, due to their genotypic differences. The highest response rate to these therapies was observed in the Japanese population and may be due to a reduced expression of EGFR associated with the longer sequence of allele 20 (the most frequent allele in Asians) unlike the shorter sequence of 16 repeats associated with white and black ancestry [56]. Skin toxicity, the most common adverse effect of EGFR inhibitors, has not been uniformly associated with tumor response. By taking into consideration the elevated expression of EGFR in epidermis [57] and the proposed effect of the (CA)n polymorphism, it seems reasonable to correlate these EGFR genotypes with sensitivity of both epidermal and tumor tissues, although other genetic determinants such as the effectors in the signal transduction cascade may also contribute to this association [56]. Furthermore, and in contrast, previously published data suggest a significant correlation between the polymorphic variations in intron 1 of EGFR and response to inhibitors. The reasons suggested by the authors for this discrepancy could be related to methodologic issues regarding the use of nonquantitative and poorly validated immunohistochemistry methods [58].

In breast cancer, allele length is inversely proportional to the level of EGFR transcription [55], and when there are 21 repeats, transcription decreases to about 80%, resulting in decreased cellular EGFR protein levels [54]. Furthermore, squamous cell histology in NSCLC is associated with higher EGFR content [49], and so it is expected to have shorter allele lengths.

In 2006, a study aimed at characterizing the frequency of EGFR polymorphisms in NSCLC specimens and determining the correlation of CA repeats with survival in the population of the Eastern Cooperative Oncology Group (ECOG) 3590 clinical trial was published [59, 60]. The ECOG 3590 clinical trial was a multicenter, randomized, prospective trial of adjuvant therapy following resection of stage II and IIIA NSCLC. Patients with complete tumor resection were randomized to receive either thoracic radiation (RT; 50.4 Gy) or RT concurrent with CT (four 28-day cycles of 60 mg/m2 cisplatin on day 1 and 120 mg/m2 etoposide on days 1–3). Survival was similar in both study arms. Of the 488 patients enrolled onto the ECOG 3590, 157 primary tumor samples were available for EGFR intron 1 analysis. In this subanalysis, it was demonstrated that patients with more than 35 (CA)n repeats in EGFR intron 1 polymorphism had a significantly longer overall survival, with a median survival of 41 months compared with 29.2 months for the patients with the 35 or fewer (CA)n alleles (p = .03). There was no difference in median survival between the groups of patients treated with RT alone, but a difference was seen between the groups in the RT-plus-CT group. Thus, although the authors concluded that EGFR dinucleotide polymorphisms (≤35 (CA)n nucleotide repeats) was a good prognostic marker, it could also be interpreted as an unfavorable predictive marker associated with the combined treatment of RT plus CT [61]. The study addressed the use of dinucleotide repeats neither as a prognostic marker per se nor as a predictive factor for benefit from EGFR-TKIs.

The EGFR regulatory region has a high content in guanine-cytosine (G-C) and multiple transcriptional start sites, but there are no TATA or CAAT boxes [62, 63]. A TATA box serves to fix the transcription initiation site [64], and most genes whose promoter regions contain a TATA box have a single RNA start site. For genes with multiple start sites, such as EGFR, the promoters are often activated by Sp family proteins [65, 66]. The main role of the Sp1 in EGFR promoter activity has been extensively described [62, 67–69], and the requirement of Sp1 for EGFR transcription is well known [70].

EGFR intron 1 is 120 kilobases (kb) long, and it is believed that the sequences around exon 1 may have a separate effect on gene regulation [70]. The (CA)n polymorphism in intron 1 of EGFR seems to be unstable, with five other frequent nucleotide polymorphisms in the 5' regulatory region, and thus may not be functional by itself. There are studies that support the hypothesis that EGFR-216G/T SNP has a functional relevance, including susceptibility to EGFR inhibitors [70]. Allele T in this polymorphism was associated with a 40% increase in EGFR expression in vivo compared with allele G. The polymorphic allele is also expected to result in a stronger correlation between Sp1 and EGFR expression, potentially resulting in a different signaling network, probably because it is located in a Sp1-binding site, which is a critical region for the promoter activity [63, 67]. Thus, it is likely that EGFR-216G/T may, at least partially, contribute to the variability of EGFR expression in malignant cells and influence the reliance of cells upon EGFR. Conversely, EGFR expression seems to manifest interindividual variability, which may be related to EGFR-216G/T polymorphism [70]. Previously identified somatic mutations in EGFR are not capable of predicting those NSCLC patients who will likely respond to EGFR-TKIs. Data from published studies demonstrated that only 81% of lung cancer patients who were treated with gefitinib or erlotinib and who experienced partial responses or significant clinical improvement had EGFR somatic mutations [71] and that not all patients sensitive to gefitinib had EGFR mutations [46]. Furthermore, it was recently suggested that these mutations are not relevant in other types of tumors [72], although there is evidence of activity in other diseases such as colon cancer and brain tumors [73]. Thus, in spite of strong association, EGFR somatic mutations are neither sufficient nor necessary for drug response [70].

EGF
The ErbB receptors are activated through binding of EGF-family growth factors that are produced by the same cells that express the ErbB receptors (autocrine secretions) or by surrounding cells (paracrine secretions) [27, 28]. Proteins belonging to this family are characterized by the presence of an EGF-like domain, which is constituted by three joined disulphide intramolecular groups, conferring linkage specificity, and additional structural motifs such as immunoglobulin-like domains, heparin-binding locations, and glycosylation sites.

The EGF gene is located in chromosome 4q25-27, and its protein may activate DNA synthesis and cellular proliferation and stimulate mitosis in epidermal cells [74, 75]. EGF is encoded by a 4.8-kb mRNA transcripted from a 110-kb gene containing 24 exons [76].

It has been proposed that the interaction between EGF and EGFR may be a factor of susceptibility and prognosis in various tumors, such as melanoma, glioblastoma multiforme, or gastric cancer [77].

It has been shown that the treatment of tumor cells with oligonucleotide antisense combinations directed toward different EGF-like growth factors resulted in synergistic antitumoral effects in different tumors [78]. Recently, it has been documented that combined therapy with the EGFR-TKI gefitinib and the monoclonal antibody anti-ErbB2 trastuzumab has a synergistic antitumor effect [77–89]. These results indicate a new possibility of treatment for cancer patients that may ultimately lead to a more efficient and prolonged control of tumor growth through the use of combinations of agents targeted toward ErbB receptors and their ligands.

EGF Polymorphisms
To the best of our knowledge, only one functional polymorphism in the EGF gene has been described and is associated with different types of tumors and with apparent functional consequences. Identified in 2002, this polymorphism is located in the 5'-untranslated region of the EGF gene. It consists of a substitution of guanine (G) for adenine (A) that leads to increased EGF expression by cultured peripheral-blood mononuclear cells. It has been identified 61 base pairs (bp) downstream of the EGF promoter and has been detected in 44% of the European white population and in almost 66% of patients with cutaneous malignant melanomas [80]. Carriers of the heterozygous G allele had a 2.7-fold relative risk for melanoma, whereas homozygous G individuals had an even higher risk compared with normal population (odds ratio, 4.9). The GG genotype was also significantly associated with a higher Breslow thickness index at the time of diagnosis [79], which is recognized as an adverse prognostic factor in malignant melanoma [81]. Nevertheless, the association between the EGF+61G/A polymorphism and the risk for malignant melanoma, as well as the association of the G/G genotype to Breslow’s depth index, was not confirmed by other studies [82–85]. Therefore, no conclusive evidence supports the role of the EGF genotype in determining the susceptibility to cutaneous malignant melanoma, and its role in prognosis remains unclear [86].

The EGF+61G/A allele was associated with increased EGF expression observed in the resected specimens of primary or secondary glioblastoma multiforme [87]. It was shown that this association is independent from EGFR overexpression or gene mutation, which could indicate that this genetic variant on EGF does not depend on EGFR genetic alteration even in cases of increased activation of the receptor. However, because the EGF+61G/A allele is associated with increased EGF expression, it may promote development and progression of glioblastoma multiforme and may ultimately be responsible for a more aggressive disease [87].

The mechanism by which increased EGF expression is associated with the polymorphism of the 5'-untranslated region of the EGF gene is currently unknown. One plausible explanation is the proximity of +61G locus to a region involved in EGF gene regulation [87]. A recent report suggests that the EGF+61G/A polymorphism could be involved in the development and malignant progression of gastric cancer [88], although another study failed to demonstrate such association [89].


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusion
Disclosure of Potential...
 References
 
Overexpression of EGFR is associated with a more aggressive phenotype, worse clinical prognosis, and chemo- and radioresistance in different solid tumors. The understanding of these molecular mechanisms has already led and, in the near future, will lead to the development of new therapies with significant clinical improvements. This is the case for EGFR inhibition in NSCLC, either by EGFR-TKIs or anti-EGFR antibodies that constitute a promising area of innovative treatment. At present, the factors that may be useful in predicting which patients will benefit from the treatment with EGFR-directed drugs is still largely unknown.

The low efficacy of some of these drugs in NSCLC patients led us to search for the explanation in patients’ genetic background and tumor characteristics, keeping in mind that intricate and complex pathways may modulate response to treatment.

Patients carrying different functional polymorphic alleles from EGFR and EGF genes may potentially respond differently to EGFR-TKIs, although this remains an unanswered question. Furthermore, there is scant information regarding the influence of genetic polymorphism on EGFR and EGF expression levels in peripheral blood and tumor tissue. Therefore, further research to understand the field of EGF and its receptor remains a priority, and more studies are necessary and underway.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusion
 Disclosure of Potential...
References
 
The authors indicate no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Conclusion
 Disclosure of Potential...
 References
 

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