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EGFR Mutations in Non–Small-Cell Lung Cancer: Analysis of a Large Series of Cases and Development of a Rapid and Sensitive Method for Diagnostic Screening With Potential Implications on Pharmacologic Treatment

From the Clinical Research Center, Center of Excellence on Aging, University-Foundation, and the Department of Surgery, University of Chieti, Chieti; Department of Surgery, University of Pisa, Pisa, Italy

Address correspondence to Antonio Marchetti, MD, Pathology Unit, Clinical Research Center, Center of Excellence on Aging (CeSI), University-Foundation, Via Colle Dell’Ara, 66013 Chieti, Italy; e-mail: amarchetti{at}unich.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non–small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method.

PATIENTS AND METHODS: We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach—direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations.

RESULTS: There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing.

CONCLUSION: Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with an extracellular ligand-binding domain and an intracellular domain possessing intrinsic tyrosine kinase (TK) activity.¹ After ligand binding, receptor dimerization leads to both activation of the TK domain and recruitment and phosphorylation of intracellular substrates, which drive normal cell growth and differentiation.^2,3 Many molecular events may lead to a persistent activation of the kinase activity, which consequently triggers a broader spectrum of downstream signal transduction pathways, including K-ras activation.^4-7 Thus, EGFR is believed to play a critical role in neoplastic progression.^8,9 Several studies reported genomic alterations of EGFR in glioblastomas in the context of the extracellular or intracellular domain.^10,11 The most common of these mutant EGF receptors, EGFRvIII, is one in which amino acids 6 to 273 of the extracellular domain are deleted. This specific mutation has been shown to promote aggressive growth of tumors in vivo. The loss of part of the extracellular domain results in a receptor that has constitutive TK activity.¹² The EGFR was found to be overexpressed in several types of tumors, including lung carcinomas.¹³ In particular, in different series of non–small-cell lung carcinomas (NSCLCs), an overexpression of the EGFR, ranging from 43% to 89%, has been reported.^14-18

The inhibition of EGFR by specific blocking agents induces apoptosis and reduces proliferation of tumor growth in different experimental models¹⁹; thus, EGFR inhibitors represent new promising targeted antineoplastic drugs.²⁰ Among them, small-molecule inhibitors of EGFR TK activity have emerged, including gefitinib (Iressa, ZD1839; AstraZeneca Inc, London, United Kingdom). This synthetic anilinoquinazoline compound, approved in Japan and the United States for relapsing patients with advanced NSCLC, acts selectively by competitive inhibition of the binding of adenosine triphosphate to the TK domain of the receptor, resulting in inhibition of the EGFR signaling pathway.²¹ In randomized phase II trials, response rates of 9% to 19% were reported with the use of gefitinib therapy in NSCLC patients.²² However, several data indicate that neither expression level nor constitutive phosphorylation of EGFR predict sensitivity to Iressa.²³ Therefore, unlike the situation for other targeted therapies, the gefinitib therapy has been given to patients with advanced NSCLC, regardless of the status of EGFR signaling. Recent data, reported simultaneously by two research groups, have shown that the presence of mutations within the EGFR gene can distinguish responders from nonresponders.^24,25 In particular, Lynch et al²⁴ found heterozygous mutations within the TK domain of EGFR in eight of nine tumors obtained from patients who had responded to gefitinib. On the contrary, no mutations were documented in seven nonresponders. Paez et al²⁵ found that five of five tumors from gefitinib-responsive patients harbored EGFR kinase domain mutations, while tumors from patients who progressed on gefitinib were not affected by mutations. In both studies, conducted by mutational analysis of the entire EGFR coding sequence, only genetic alterations in exons 19, 21, and 18 were found. The main goal of this study was to evaluate the actual prevalence of EGFR mutations in lung cancer and to develop a sensitive method for rapid screening of mutations. We have investigated a large series of consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 by a dual technical approach: direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation (SSC) polymorphism (SSCP) analysis. In addition, we have examined the relationship between EGFR mutations and several clinicopathological parameters, including mutations in the K-ras gene, a downstream component of the EGFR activation cascade.²⁶

	PATIENTS AND METHODS

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Patients and Tissues
The tumors for this study were obtained from 860 consecutive NSCLC patients surgically treated at the Department of Surgery, University of Pisa (Pisa, Italy), and at the Department of Surgery, University of Chieti (Chieti, Italy), between July 1998 and December 2002. Informed consent was obtained from all patients enrolled. In each case, tumor and macroscopically normal lung tissue samples (taken as far as possible from the neoplastic area) were snap-frozen in liquid nitrogen within 10 minutes of excision and stored at –80°C. Immediately adjacent pieces of tumor and normal tissue were fixed and processed for light microscopy. In all tumor specimens, the amount of tumor cells equaled or exceeded 80% of the overall sample, confirmed by histopathologic examination. Similarly, all the macroscopically normal samples were judged to be benign.

The study population consisted of 748 men (87%) and 112 women (13%), with a mean age of 62.7 years (range, 32 to 85 years; Table 1). Patient stage at the time of diagnosis was determined according the TNM staging system²⁷: 490 patients (57%) were classified at stage I; 121 (14%), at stage II; and 249 (29%), at stage III. Histological type was determined according to WHO criteria²⁸: 454 tumors were squamous cell carcinomas (53%), 289 were adenocarcinomas (34%), 86 were bronchioloalveolar carcinomas (10%), and 31 were large-cell carcinomas (4%). Histocytological subtyping of bronchioloalveolar carcinomas (BACs), according to Barkley and Green,²⁹ revealed that 69 (80%) were nonmucinous BAC, and 17 (20%) were mucinous BAC. According to smoking history, deduced from anamnestic data, 467 patients (55%) were smokers, 278 (32%) were former smokers (stopped smoking at least 1 year before the diagnosis of lung cancer), and 115 (13%) were nonsmokers. The possibility of lung metastasis from occult gastrointestinal malignancies was ruled out by clinical examinations, including abdominal computed tomography scans.

A nonradioactive SSCP assay was devised to screen for mutations in exons 18, 19, and 21, as previously described,³⁰ with the following modifications. After completion of the PCR reaction (performed as reported above, in a volume of 30 µL), the product was diluted 1:5 in loading buffer (95% formamide, 2 mmol/L EDTA, pH 8.3). Fifteen µL of the diluted samples were denatured (5' at 90°C), immediately cooled on ice, and loaded onto a nondenaturing polyacrylamide gel. The concentration of acrilamide was 10% for the screening of exon 19, and 12% for the screening of exons 18 and 21. Tumor samples were loaded side by side with the corresponding normal lung control tissue. Electrophoresis was carried out for 14 hours at 20°C at 3W. On complete migration, the gels were subjected to silver staining using the PlusOne Silver Staining Kit (Amersham Pharmacia Biotech, Piscataway, NJ). Positive cases were reamplified in the same experimental conditions, and subjected again to SSCP to confirm the mutations. The shifted bands were removed from the gel, and the recovered DNA was amplified in duplicate and subjected to direct sequencing as reported earlier.

K-ras Gene Analysis
The following primers were used to amplify the K-ras gene around codon 12: 5'–GGCCTGCTGAAAATGACTGA–3' and 5'–TGATTCTGAATTAGCTGTAT–3'. The PCR reaction was programmed as follows: initial denaturation, 4 minutes at 94°C; amplification, 30 seconds at 94°C, 30 seconds at 54°C, and 1 minute at 72°C for 35 cycles; elongation, 10 minutes at 72°C.

The amplified products of the PCR reaction were denatured and blotted onto nylon membranes pre-wetted with 10x SSC (1x SSC is 150 mmol/L NaCl, 15 mmol/L Na citrate at pH 7.6). Each membrane was then hybridized separately with ³²P-labeled mutation specific oligodeoxynucleotide probes.³¹ The hybridization was performed for at least 1 hour at 56°C in a specific solution (3M tetramethylammonium chloride, 50 mmol/L Tris-HCl, 5 mmol/L EDTA, 1% sodium dodecyl sulfate, and 1% milk protein). The membranes were then washed at 63°C in 5x sodium chloride-sodium phosphate-EDTA (SSPE) (1x SSPE is 180 mmol/L NaCL, 8 mmol/L NH₂P0₄, 1 mmol/L EDTA) and 0.1% sodium dodecyl sulfate for 20 minutes, and subsequently rinsed in 2x SSC at room temperature. The filters were exposed to Kodak XAR 5 (Eastman Kodak, Rochester, NY) films for 1 day at –70°C.

Statistical Analysis
The variables measured in the study were investigated for association by using the Fisher’s exact test or ² test as appropriate. The associations of EGFR mutational status, as a dependent variable, with histologic type (BAC v conventional lung adenocarcinoma [CLA]), sex (male v female), and smoking history (smoker or former smoker v nonsmoker) were also investigated by logistic regression analysis to account for the effect of the different variables. A P value less than .05 was considered significant.

	RESULTS

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EGFR Mutations
The genomic status of the TK domain of the EGFR gene was evaluated in a series of 860 primary NSCLCs. Exons 18, 19 and 21, which were known to contain all the EGFR mutations identified in lung cancer patients, were subjected to mutational analysis. We decided to use two screening procedures: PCR amplification and direct sequencing of the PCR products; and PCR amplification followed by SSCP analysis and sequencing of the shifted bands. There were no EGFR mutations in 454 squamous carcinomas and 31 large-cell carcinomas investigated. A total of 39 mutations were found in the series of 375 patients affected by lung adenocarcinomas (10%). All the mutations identified were not present in the DNA of normal lung tissue from the same patients. Eighteen mutations (46%) were located in exon 19; 18 (46%) in exon 21; and three (8%) in exon 18.

Direct sequencing of PCR products allowed detection of eterozygous mutations in 31 adenocarcinomas (8%): 18 (58%) in exon 19; 11 (36%) in exon 21; and two (6%) in exon 18. SSCP analysis confirmed all the results obtained by sequencing, moreover it allowed identification of additional eight mutations: seven in exon 21 and one in exon 18. No false-positive or false-negative results were obtained using the SSCP assay. The mutations identified only by the SSCP screening were all point mutations. SSCP-positive cases were repeated in order to confirm the data and were subjected to amplification in replicate and direct sequencing of the shifted bands.

Of the 39 mutations identified, 18 (46%) were in frame deletions in exon 19, and 21 (54%) were aminoacidic substitutions in exons 21 and 18 (Table 2). The deletions "L747_T751del" and "L747_P753del" were associated with the insertion of a serine residue, resulting from a novel codon at the deletion breakpoint, whereas the deletion "L746_T751del" was associated with an alanine residue. Deletions "E746_T751del (ins ala [insertion of alanine residue])" and "L747_E749del" have never been described before. Interestingly all the deletions overlapped and shared the deletion of two amino acids, arginine and glutamic acid at codons 748 and 749. Among the amino acid substitutions, the leucin to arginin mutation (L858R) was found in 17 (44%) of the 39 tumors, representing the main hot spot mutation in the EGFR gene. We report a new amino acidic substitution at codon 858, L858M (Fig 1G). This rare mutation confirms the crucial role of codon 858 in lung cancerogenesis. Three missense mutations were found at codon 719, resulting in the substitution of cysteine for glicine.

View larger version (47K): [in this window] [in a new window]   Fig 1. Single-strand conformation polymorphism and correspondent sequence analysis of mutations found in the EGFR gene. (A to D) Cases with the more frequent deletions observed in exon 19; (E) point mutation 2573 T > G (L858R); (F) point mutation 2155 G > T (G719C); (G) point mutation 2572 C > A (L858M). T, tumor sample; N, healthy lung sample.

Correlations of EGFR Mutations With Clinicopathologic Data
Among adenocarcinomas, the distribution of EGFR gene mutations was significantly different between BACs and CLAs. They were present in 22 (26%) of 86 BACs and in 17 (6%) of 289 CLAs; P = .000002 (Table 3). All 22 mutations detected in BAC were seen in the nonmucinous subtype; P = .005 (Table 4).

EGFR mutations were more frequent in women (21 of 71; 30%) than in men (18 of 304; 6%); P = .0000002. However, among the 39 tumors with mutations, 18 (46%) were from men, and 21 (54%) were from women (Table 3). This apparent similar distribution of EGFR mutations in men and women is ascribable to the greater number of men in our series of patients.

In this series of tumors, the BAC and CLA histotypes were also investigated for K-ras mutations at codon 12 by the allele-specific olygonucleotide assay. All of the tumors affected by EGFR were found to be negative for K-ras mutations, whereas tumors negative for EGFR mutations showed a K-ras mutation in 32% of cases (P = .000001; Table 3). The prevalence of K-ras mutations was 29% in CLA and 27% in BAC. In the 108 tumors with mutated ras, the normal DNA sequence GGT (glycine) at codon 12 was altered to TGT (cysteine) in 57 cases (53%), to GTT (valine) in 38 cases (35%), and to GAT (aspartic acid) in 13 cases (12%). The frequency of K-ras mutations, as well as the distribution of the different types of mutations at codon 12, did not vary significantly between BAC and CLA (P = .7 and P = .5, respectively). Fourteen percent of nonmucinous BACs carried a K-ras point mutation at codon 12, while mucinous BACs showed K-ras mutations in 76% of cases (P = .00002; Table 4). The other clinocopathologic parameters, including age, tumor size, nodal status, and tumor stage were not significantly associated with EGFR mutations (Table 3).

The association of EGFR mutations, as a dependent variable, with tumor histotype, sex, and smoking history, was also evaluated by logistic regression analysis to take into consideration the reciprocal effects of the covariates investigated. As presented in Table 5, EGFR mutations were found to be independently associated with the BAC histotype, the absence of smoking history, and female sex (odds ratios: 4.542, 3.632, and 2.895, respectively).

	DISCUSSION

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The gene was not mutated in squamous cell carcinomas and large-cell carcinomas, whereas approximately 10% of adenocarcinomas showed the mutation. Among adenocarcinomas, the prevalence of EGFR mutations was significantly different in CLA and BAC. While in CLA, EGFR mutations were found in only 6% of cases, 26% of BAC tumors harbored EGFR mutations. Clinical reports indicate that patients who experienced a response to EGFR TK inhibitors often had a bronchioloalveolar histology.^32-36 Studies with oral EGFR TK inhibitors (gefitinib, erlotinib), specifically on BAC, are ongoing. Preliminary results of the Southwest Oncology Group S0126 trial, evaluating gefitinib in BAC, indicate a response in previously untreated patients in 21% of cases.³⁷ Preliminary results of an erlotinib trial in BAC indicate a response rate of 26%.³⁸ Since these frequencies are very similar to the frequency of EGFR mutations observed in our series of BAC, we suggest that about one fourth of BACs may respond to EGFR TK inhibitors because of mutations affecting the gene.

Tumors with EGFR mutations were more often T1, but data were not significant. There were no differences in the propensity to metastasize (N status) and in the pathological stage between tumors with and without EGFR mutations.

In univariate analysis, EGFR mutations were significantly more frequent in women and in nonsmokers. These results are in keeping with those recently reported by Lynch et al,²⁴ Paez et al,²⁵ and Pao et al³⁹ in smaller series of patients. In this regard, it is important to note that in clinical trials, a partial or complete clinical response to EGFR TK inhibitors has been observed more frequently in women and nonsmokers.³⁵ In our study, when the histotype, sex, and smoking history were tested in a multivariable analysis against the presence of mutations in EGFR as dependent variable, the bronchioloalveolar histology, a history of never having smoked, and female sex, remained significant. Of these three variables, the most strongly related to the presence of EGFR mutations was BAC histotype, followed by smoking history. The highest fraction of EGFR mutations was observed in nonsmokers affected by BAC—13 (57%) of 22 cases. These results are in agreement with recently published data indicating that BAC subtype and smoking history independently predict sensitivity to gefitinib in NSCLC patients.^34,36

BACs are lung tumors believed to arise from bronchiolar and alveolar epithelium, with a characteristic growth pattern along the alveolar walls.⁴⁰ Compared with other subtypes of NSCLC, BAC is characterized by distinct clinical presentation, radiographic appearance, and natural history.⁴¹ Patients with BAC tend to be younger at diagnosis and are more likely to be females and nonsmokers when compared with other NSCLC patients.⁴¹ These differences raise the question of whether BAC represents a separate biologic entity. We have previously shown that there are differences in the distribution and/or quality of p53, K-ras, and FHIT mutations between BAC and CLA.^31,42,43 In keeping with these results, the present data suggest that BAC is a distinct biologic entity of lung carcinoma.

BACs are histologically classified into two major subsets: nonmucinous and mucinous.²⁹ The mucinous type is characterized by tall columnar cells, similar to goblet cells, with abundant apical mucin-rich cytoplasm. In nonmucinous BAC, the neoplastic cells are cuboidal to columnar, and frequently show apical snouts and a hobnail appearance, resembling Clara cells. All the EGFR mutations found in BAC were seen in the nonmucinous type. Eighteen (35%) of 51 nonmucinous BACs had mutations in EGFR. Conversely, mucinous BAC, always negative for EGFR mutations, were frequently affected by codon 12 mutations of the K-ras gene. These observations suggest a mucinous and nonmucinous pathway of BAC carcinogenesis, characterized by specific genetic changes, in agreement with our previous observations.^31,42 However, due to the limited number of mucinous BACs investigated, additional studies are required to confirm these data. EGFR mutations and K-ras mutations were found to be mutually exclusive in that none of the 39 tumors with EGFR mutations had a concomitant mutation in K-ras. This inverse relation can be explained considering that these two genes belong to the same signaling cascade. Since mutations of EGFR and K-ras genes seem to be related to the development of different BAC types, we speculate that they could have different effects on tumor morphology; alternatively, they could affect different cells (goblet cells, Clara cells) or cell precursors.

In our series of tumors, only 6% of CLA harbored EGFR mutations. However, since CLA was more frequent than BAC, 44% of the tumors with mutated EGFR were conventional adenocarcinomas. These data indicate that for an accurate detection of EGFR mutations in lung cancer, all patients affected by BAC and CLA must be subjected to mutational screening. A large-scale screening requires a rapid and sensitive technique. In the present study, we describe a reliable SSCP assay for the detection of mutations occurring in the EGFR TK domain. The SSCP analysis was found to be more sensitive than direct sequencing of PCR products, allowing identification of mutations that were hardly detectable or undetectable (21% of cases) by direct sequencing. Mutations missed by direct sequencing were all point mutations. These results are in accordance with previous data published by our group and others, indicating that PCR-SSCP can be more sensitive than direct sequencing. The PCR-SSCP technique is able to detect mutations in samples containing as little as 10% mutated DNA, whereas direct sequencing requires at least 30% of mutated DNA in the sample.^44,45

In our series of cases, we found three new mutations (two new types of deletions and a new aminoacid substitution at codon 858) and confirmed the presence of several hot spot mutations. In particular, we found that the leucin to arginin substitution at codon 858 is the most frequent mutation (46% of cases). This point mutation, together with the deletion "E746_A750del" accounts for approximately 70% of the mutations affecting the TK domain of EGFR.

Six SSCP patterns, corresponding to the hot spot mutations observed, were identified. Using these patterns, more than 90% of the mutations in the EGFR gene can be immediately recognized by SSCP analysis. No false-positive or false-negative results were obtained using the SSCP assay. In addition, we have previously reported that the PCR-SSCP assay can be performed on formalin-fixed, paraffin-embedded small biopsies,⁴⁶ allowing the detection of mutations from minimal amounts (< 1 µg) of starting DNA. We are confident that this method, followed by sequencing of the shifted bands, can be successfully used for rapid screening of patients with non–squamous cell lung carcinomas.

In conclusion, mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in the BAC histotype, in nonsmokers, and in females, independent from K-ras mutations, that is likely to respond to EGFR tyrosine kinase inhibitors. The SSCP assay described is a rapid and reliable method for the screening of EGFR kinase domain mutations in lung cancer patients.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by grants from Centro Nazionale Ricerche–Ministero dell’Università e della Ricerca Scientifica e Tecnologica(CNR-MURST), Center of Excellence on Aging (CeSI), and Fondo per gli Investimenti della Ricerca di Base (FIRB).

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 5, 2004; accepted November 2, 2004.

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