Status Of EGFR Genic Mutation And Copy Number In Lung Adenocarcinoma Patients

Background:Lung cancer is the most common malignancy in the world. Human lung cancers are classified into twomajor types, small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), the latter consistingof several types, mainly adenocarcinoma and squamous cell carcinoma. Previously, squamous cellcarcinoma was the predominant form of NSCLC, but in the last few decades it has been replaced byadenocarcinoma. Lung cancer is the largest single cause of death from cancer in the world, with a mortalityof1.3million annually. The high mortality is mainly because of early development of systemic disease andresistance to currently available treatment strategies. Novel strategies are thus required to improve patientoutcomes. With further research on the epidermal growth factor receptor (EGFR), targeting this receptormay provide a unique approach for treating cancers. This concept led to the development and regulatoryapproval of small-molecule EGFR TK inhibitors (TKIs) such as gefitinib and erlotinib; however, clinicaltrials have revealed significant variability in the response to TKIs. Clinical responsiveness to gefitinib wasassociated with somatic mutations in the TK domain of EGFR gene in NSCLCs. In addition, some studieshad reported that patients with an amplification of EGFR gene in lung cancer tissues were shown to bemore responsive to EGFR-TKI than patients with normal EGFR gene copy numbers.Objective:It is likely that mutations and high gene copy numbers are both important in determining EGFR-TKIsensitivity. The aim of the present study was to investigate the clinicopathologic features associated withthe mutation status and gene copy number of the EGFR gene in NSCLC patients, and the correlationbetween them., in addition, to define the prognostic impact of mutations and increased copy of EGFR gene.Methods:150paraffin-embedded tissues were collected from patients diagnosed with lung adenocarcinomafrom September2008to February2011. A total of150patients consisted of80males and70females,63ever smokers and87never smokers,12stage Ⅰ、16stage Ⅱ、70stage Ⅲ and52stage Ⅳ. Real-timePCR was used to detect EGFR gene mutation after DNA was extracted, and the gene copy number statuswere determined by FISH (Fluorescence in Situ Hybridization). SPSS13.0software for inspection andχ2 test were used to analyze the clinical features associated with the mutation and gene copy number status,and the correlation between them. Survival estimates were calculated with the Kaplan-Meier method andcompared using the log-rank test.Results:Among150patients, EGFR gene mutation was found in63cases, the mutation rate was42.0%. Themutation rate in males and females were31.2%and54.3%respectively; and in ever smokers and neversmokers were31.7%and49.4%. The differences have statistically significant(P＜0.05). The presence of anEGFR mutation was not associated with age, histological grade. In addition, the in-frame deletions in exon19were significantly more frequent in males while an L858R mutation in exon21was more frequentlyfound in females (P=0.020). FISH positivity was found in68cases of150samples, the rate was45.3%.FISH positivity was not associated with gender, age, smoking status and histological grade(P>0.05). Themutations were associated with EGFR high copy number (P＜0.05). Furthermore, a high EGFR gene copynumber might have short survival (P=0.026).Conclusions:EGFR mutations were significantly related to clinical features. The mutations were more frequentlyfound in women than in men, in never smokers than in ever smokers. These features are good predictors ofEGFR mutations. In addition, the in-frame deletions in exon19were significantly more frequent in maleswhile an L858R mutation in exon21was more frequently found in females. Our findings suggest thatindividual EGFR exons may have differing pathogenesis of mutations.EGFR mutations were associatedwith gene copy number status, Combered analysis of EGFR mutation and gene copy number may be morehelpful for selecting patients who may benefit anti–EGFR therapy. FISH–positive cases were significantlycorrelated with worse prognosis.