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      Comparable rate of EGFR kinase domain mutation in lung adenocarcinomas from Chinese male and female never-smokers

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          Abstract

          Lung cancer patients with the epidermal growth factor receptor (EGFR) kinase domain mutations frequently show good responses to small molecule tyrosine kinase inhibitors, including Iressa and Tarceva, in clinical studies 1, 2, 3 . Previous studies have demonstrated that EGFR kinase domain mutations are commonly observed in lung adenocarcinomas, never-smokers, East Asian, and females 4, 5, 6, 7, 8 . In contrast to caucasion females, most East Asian females do not smoke, while tobacco smoking is very common in the male population. This gender-associated tobacco usage may bias the EGFR mutation incidence in lung adenocarcinoma patients. Here we analyzed the EGFR mutation rate together with gender and smoking status in Chinese lung adenocarcinoma patients. Interestingly, our results showed a comparable rate of EGFR kinase domain mutations in lung adenocarcinomas from Chinese male and female never-smokers. We have sequenced the EGFR kinase domain using cDNA extracted from 224 lung adenocarcinomas continuously collected from September 2007 to October 2009 at Shanghai Cancer Hospital, Fudan University, with patient consent. Clinical information including age, smoking history, stage and lung tumor differentiation status is listed in Table 1. All patients were Chinese; they came from Shanghai and 10 other provinces. About 62% (139/224) of the lung adenocarcinomas were from never-smokers, and about 38% (85/224) were from ever-smokers (Table 1). Only 2 of 110 Chinese females smoked, while 83 of 114 males were ever-smokers. About 63% (142/224) of lung adenocarcinomas harbored EGFR kinase domain mutations. Without considering gender-associated tobacco usage, our data were similar to those of previous reports 4, 5 . EGFR kinase domain mutations tended to occur in never-smokers (75.54%) more frequently than in ever-smokers (43.53%), and female patients had a higher mutation rate of the EGFR kinase domain (75.45%) than did male patients (51.75%) (P<0.01). We then analyzed the association of EGFR kinase domain mutations with gender in never-smokers and ever-smokers separately. About 55% (46/83) of male ever-smokers had EGFR mutations (Table 1). The only two female smokers had no EGFR mutations. Interestingly, a comparable EGFR kinase domain mutation rate was found in both male never-smokers (70.97%; 22/31) and female never-smokers (76.85%; 83/108) (Table 1). These data clearly showed that gender did not influence EGFR kinase domain mutation rates in never-smoker patients with lung adenocarcinomas. The low rate of EGFR mutations in males could possibly be ascribed to the low number/percentage of male never-smoker patients with lung adenocarcinomas. Similar conclusion has been drawn using Japanese clinical samples 9, 10 . Although Chinese and Japanese patients are both from East Asia, it has not been conclusively demonstrated that Japanese lung cancer patients are biologically the same as Chinese lung cancer patients. Our study using 224 lung adenocarcinoma specimens mainly from eastern China extends previous studies 6, 7 and corroborates the notion that gender does not play a significant role in the distribution of EGFR mutations in lung adenocarcinoma. Further studies to include other areas in China and that significantly increase the patient number will be very helpful to solidify and extend our results. The status of EGFR kinase domain mutation has been proposed as one of most important factors used for Iressa or Tarceva treatment decision-making in clinic 11 . Based on our findings in this study, not only Chinese female never-smokers but also male never-smokers are likely to benefit from EGFR-targeted therapy.

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          Most cited references 11

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          Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

          Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
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            EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

            Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
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              EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.

              Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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                Author and article information

                Journal
                Acta Pharmacol Sin
                Acta Pharmacol. Sin
                Acta Pharmacologica Sinica
                Nature Publishing Group
                1671-4083
                1745-7254
                May 2010
                26 April 2010
                : 31
                : 5
                : 647-648
                Affiliations
                [1 ]Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences , Shanghai 200031, China
                [2 ]Thoracic Surgery, Shanghai Cancer Hospital, Fudan University , Shanghai 200032, China
                [3 ]Vanderbilt-Ingram Cancer Center , 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232–6307, USA
                Author notes
                aps201043
                10.1038/aps.2010.43
                3990499
                20418893
                Copyright © 2010 CPS and SIMM
                Categories
                Letter to the Editor

                Pharmacology & Pharmaceutical medicine

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