Significance of epidermal growth factor receptor gene mutations in squamous cell lung carcinoma

Epidermal growth factor receptor (EGFR) gene mutations have been reported to be clinically significant in non-small cell lung cancer (NSCLC). However, because most previous studies focused only on adenocarcinomas, EGFR mutations in other histotypes are poorly investigated. We evaluated the frequency of EGFR gene mutations in squamous cell carcinoma (SCC) and its clinicopathological features. In total, 89 frozen tumor specimens that had been first diagnosed as SCCs, were examined for EGFR mutations in exons 19 and 21 using direct sequencing, PNA-enriched sequencing and SmartAmp2. Additionally, pathological investigation, including immunostaining for p63 and TTF-1, alcian blue staining and EGFR mutation-specific immunohistochemistry in mutation-positive samples was also performed. The frequency of EGFR mutations was 5.6% (5/89); all mutations were deletions in EGFR exon 19. Immunohistological investigation of these samples revealed that two of five were positive for p63 and TTF-1 staining, and showed production of mucin, as evidenced by alcian blue staining. Consequently, three of the samples were considered to be true SCC at final pathological diagnosis, while the remaining two samples were revised to adenosquamous carcinoma and adenocarcinoma. The final frequency of the EGFR mutations in true SCC was 3.4% (3/87). In conclusion, EGFR mutations were found in a small, but significant, number of SCC tumor samples and thus EGFR mutational analysis was useful in the accurate diagnosis of SCC. Our data demonstrate that EGFR mutational analysis should be performed not only in adenocarcinoma, but also in SCC to allow accurate diagnosis and treatment.     

Different epidermal growth factor receptor gene mutations in a patient with 2 synchronous lung cancers

Recently, the frequency of lung adenocarcinoma has been increasing among nonsmokers, though the etiology remains unclear. Mutations of the epidermal growth factor receptor (EGFR) gene are frequently detected in the lung adenocarcinomas seen in nonsmokers. Thus, EGFR mutations can be implicated in carcinogenesis of lung adenocarcinoma. Herein, we report a case of 2 synchronous lung adenocarcinomas composed of 2 distinct pathological subtypes with different EGFR mutations: homozygous deletion in exon 19 in the papillary subtype of adenocarcinoma and a point mutation of L858R in exon 21 in the tubular adenocarcinoma. These findings suggest that specific mutations can occur randomly in the EGFR hot spot, and that these EGFR mutations can contribute to the distinct carcinogenic process of each adenocarcinoma.     

Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers

Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers have generated enormous interest, because they predict for sensitivity to TK inhibitors (TKIs). While mutational status is of great importance in determining response to TKIs, it is not the sole factor, and evidence is accumulating that EGFR gene amplification, other members of the EGFR family (HER2, HER3) and genes downstream of EGFR signaling (KRAS, BRAF), may be involved in cancer pathogenesis and the response of TKIs. EGFR mutations occur in highly selected subpopulations of lung cancer patients: adenocarcinoma histology, never-smoker status, East Asian ethnicity and female gender. The recent finding of "a resistance associated" mutation for TKIs also provides new insights into this complicated mechanism. Thus, molecular-based studies to analyze the biological functions and to assess TKI sensitivity depending on the type of mutations are required. Epidemiological studies to identify possible carcinogenic factor(s) affecting different subpopulations are also of interest. In addition, for optimal therapeutic approach a comprehensive understanding of the genes related to EGFR signaling pathway, including RAS/RAF/MAPK and PI3K-AKT pathways, are required.     

Prognostic value of epidermal growth factor receptor mutations in resected lung adenocarcinomas

In this study, we investigated the associations of polymorphisms in glutathione-S-transferases (GSTs) genes that are GSTM1, GSTT1, and GSTP1, with sporadic colorectal cancer (CRC). Hundred and fifty patients with CRC and 128 healthy controls were genotyped. DNA was isolated from blood samples. Polymorphisms were assessed by polymerase chain reaction–restriction fragment length polymorphism-based methods and polymerase chain reaction multiplex. Logistic regression analyses showed significant risk for CRC associated with GSTP1 homozygotes for Val-105 (OR 4.82; 95 % CI 1.97–11.80) or for individuals who possessed at least one Val-105 allele (OR 2.54; 95 % CI 1.751–3.703). There were no statistically significant differences in the frequency of GSTM1- and GSTT1-null genotypes (p > 0.05). The GSTM1-null was found in 70.47 % of all cases and 70.07 % of controls (OR 0.61; 95 % CI 0.33–1.12). The GSTT1-null genotype was found in 38.77 % of cases and 49.22 % of controls (OR 1.53; 95 % CI 0.94–2.47). No effect of any genotype for GSTM1 and GSTT1 on CRC was detected. But then an association between the polymorphism of the GSTP1 and the CRC susceptibility was detected.     

非小细胞肺癌原发灶与相应转移灶之间EGFR基因突变状况的不一致性研究

背景与目的表皮生长因子受体(epidermal growth factor receptor,EGFR)突变是晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者获益于酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)治疗的预测因子,本研究旨在探讨NSCLC原发灶与相应转移灶之间EGFR基因突变状况的不一致性。方法应用TaqManRT-PCR的方法检测35例病理确诊为NSCLC患者原发灶和相应转移灶的EGFR基因突变状况。结果原发肺癌病灶中有29例为EGFR基因突变型,余下6例为EGFR野生型。35例转移灶中18例为EGFR基因突变型,17例为EGFR野生型。35对配对标本中,11对(31.43%)标本出现原发灶EGFR基因突变,而转移灶为EGFR基因野生型,18对原发灶及转移灶均为EGFR基因突变型,且突变具体位点相同,6对原发灶及转移灶均为EGFR基因野生型。NSCLC原发灶与转移灶的EGFR基因表达不一致率为31.43%(11/35,P=0.008)。结论 NSCLC原发灶与转移灶的EGFR基因表达存在不一致性。     

Update on epidermal growth factor receptor mutations in non-small cell lung cancer.

In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have examined the biological properties that such mutations confer as well as the clinical relevance of these mutations in patients with non-small cell lung cancer. Although a tremendous amount of knowledge has been gained in the past 2 years, there remain a number of important epidemiologic, biological, and clinical questions.     

Mutation of epidermal growth factor receptor gene in adenosquamous carcinoma of the lung

We have investigated 26 adenosquamous lung cancer tissues and found that four EGFR mutations were mainly in female and non-smoker lung cancer. However, EGFR mutation at kinase domain was exclusive with K-ras mutation. However, smoking and gender status could affect the occurrence of EGFR mutation. There was no difference in EGFR mutation status if analysis was performed in never smoker female subgroup.     

Frequency of epidermal growth factor receptor mutations in Bangladeshi patients with adenocarcinoma of the lung

Background

Worldwide studies on lung adenocarcinoma have demonstrated a genetic divergence of the epidermal growth factor receptor (EGFR) pathway according to ethnicity, such as higher frequency of activated EGFR mutations among East Asian patients. However, such information is still lacking in some developing countries.

Methods

We investigated the frequency of EGFR mutations among Bangladeshi patients with adenocarcinoma of the lung. Fine-needle aspiration tissue samples were collected from 61 Bangladeshi patients. Polymerase chain reaction–single-strand conformation polymorphism was performed on extracted DNA for mutational analysis of EGFR exons 19 and 21.

Results

EGFR mutations were found in 14 of 61 (23.0 %) Bangladeshi patients. There was no significant difference in EGFR mutation rate with regard to patient’s age, sex, smoking history, clinical stage of lung cancer, subtypes of adenocarcinoma, and tumor differentiation.

Conclusion

The present study revealed that the EGFR mutation rate in Bangladeshi patients with adenocarcinoma of the lung was higher than in African–American, Arabian, and white Caucasian patients, and was lower than in East Asia.     

扩增耐突变系统对非小细胞肺癌表皮生长因子受体基因突变的检测

目的:探讨扩增耐突变系统检测非小细胞肺癌(NSCLC)患者肿瘤组织EGFR基因突变的应用价值.方法:选取70例NSCLC患者的病理切片,提取基因组DNA,分别使用EGFR外显子19和21突变检测试剂盒检测EGFR外显子19和21的突变情况,并结合临床资料进行分析.结果:70例肺癌组织中检出EGFR基因突变29例,基因突变检出率为41.4％,其中外显子19突变20例(69.0％),外显子21突变9例(31.0％);腺癌基因突变23例(79.3％),检出率为51.1％;鳞癌基因突变6例(20.7％),检出率为24.0％;肺泡癌基因突变4例(13.8％),检出率为66.7％.女性、不吸烟和肺腺癌患者的EGFR 2个外显子基因突变率均较高,P＜0.01.结论:NSCLC患者EGFR基因突变主要表现为外显子19和21的突变,女性、肺腺癌和不吸烟的患者多见.     

Heterogeneity of epidermal growth factor receptor mutations within a mixed adenocarcinoma lung nodule

It has been proposed that stepwise progression occurs from atypical adenomatous hyperplasia (AAH) through bronchioloalveolar carcinoma (BAC) to invasive lung adenocarcinoma. However, the underlying molecular mechanisms have not been identified. We report a patient with a mixed adenocarcinoma of the lung that had different EGFR mutations in the papillary subtype, the acinar subtype, and the surrounding AAH and BAC areas. EGFR mutations may accumulate during tumor progression and lead to heterogeneity of EGFR mutations within the tumor.     

Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma

Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4?%). EGFR mutation was found to be significantly related to women (P?=?0.0070), never-smokers (P?<?0.0001), and tumors without vascular-poor area (P?<?0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers (P?=?0.0046), lack of vascular-poor area (P?=?0.0001), and tumor size >30?mm (P?=?0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4?%), 19 of 36 never-smokers with vascular-poor area (52.8?%), 19 of 37 current or former-smokers without vascular-poor area (51.4?%), and 16 of 54 current or former-smokers with vascular-poor area (29.6?%). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.     

A useful protocol for analyses of mutations of the epidermal growth factor receptor gene

Recent studies have reported that mutations of the epidermal growth factor receptor (EGFR) gene are associated with the responsiveness of tyrosine kinase inhibitors (TKIs), which are molecular targets for non-small cell lung cancer (NSCLC). To provide genetic analyses for NSCLC patients, a simple and reliable method using paraffin-embedded materials is needed. The DEXPAT DNA extraction kit was used for DNA extraction from paraffin-embedded materials. DNA was amplified using the nested PCR technique, then analyzed by direct sequencing for EGFR mutations (exons 18 to 21). The phenol/chloroform extraction for DNA was also performed for comparison. When the DEXPAT kit was used, distinct bands were observed in all products after nested PCR assays of paraffin-embedded materials. Distinct sequencing signals were obtained. Results from the sequencing analysis of paraffin-embedded materials and frozen materials were completely concordant. The current study suggests that DNA extraction with the DEXPAT kit followed by nested PCR is a simple and reliable technique for analyzing the EGFR gene status with paraffin-embedded samples.     

Targeting epidermal growth factor receptor in lung cancer

Among the most promising agents in clinical development to treat non-small-cell lung cancer (NSCLC) are the epidermal growth factor receptor (EGFR) targeting agents. A series of recent studies have demonstrated the activity of anti-EGFR targeted therapies for NSCLC. In advanced NSCLC that is refractory to chemotherapy, antitumor responses have been reported with EGFR tyrosine kinase inhibitors (ZD1839 and OSI-774). The role of ZD1839 and OSI-774 as possible additions to standard chemotherapy in the first-line setting has also been evaluated, and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit. Other areas of research involve looking at the role of EGFR tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies. These exciting results and plans are further complemented by an emerging number of compounds in clinical development, including both monoclonal antibodies (ie, IMC-C225) and other tyrosine kinase inhibitors, directed at the EGFR.