Study On The Relationship Between The Expression Of HSP90α In Non-small Cell Lung Cancer With EGFR Mutations In Lung Adenocarcinoma

Backgroud: In most parts of our country,the incidence and mortalityrates of lung cancer occupies the first or second position in malignant tumors,lung cancer has become a threat to human health and one of the deadly killer.Relevant data show that80%new cases of cases of lung cancer are non-smallcell cancer(NSCLC). With the development of Medical Techniques,thetreatment strategy for lung cancer are still surgery, radiotherapy andchemotherapy etc, haven’t been significantly improved,Five-year survival ratehas also not improved. In recent years, people are actively exploring to findingnew treatments for lung cancer. With the development of molecular biology inlung cancer,we find that the sensitivity of chemotherapy drug contact withcertain gene expression in cells.Anti-tumor effects of chemotherapy areclosely related to some genes overexpression or polymorphism. By detectingcertain genetic expression in tumor tissue，we can use chemotherapeuticsreasonably and make treatment targeted，thus reduce the physical damage ofineffective medicationand patients live more longer. The present besttreatment for tumor is individual comprehensive therapy，so，finding lowertoxicity and efficient chemotherapy drugs are more necessary. Tumor-targetedtherapy drugs,it’s a antitumor drugs who have lower toxicity and higherefficacy,it’s alsothe most advanced drugs and has been used in the treatmentof a variety of malignant tumors. EGFR-TKI is a type of targeted therapy fornon-small cell lung cancer, such as Gefitinib, Erlotinib etc，have been usedfor clinical treatment,Some patients with NSCLC benefit from treatment withthese drugs. Effective rate of EGFR-TKI over80%in NSCLC with EGFRMutations,as for the patients who have non-EGFR mutations the Efficientalmost zero.So,EGFR mutations is a prerequisite for the use of EGFR-TKI. As the use of EGFR-TKI in clinic,we find that patients treated by these durgs,sooner or later appear in with drug resistance. Therefore, it is imperative tofind new therapies for patient who has EGFR-TKI drug resistance. With thestudy on EGFR mutations in NSCLC, found the mainly EGFR mutations.arein lung adenocarcinoma, the following studies on EGFR-TKI were almostconducted in adenocarcinoma. EGFR mutations rates are different, indifferent regions of the world, in Asia ares, non-smoking,female,and lungadenocarcinoma patients have a higher EGFR mutations rates.Research indicates that heat shock protein90inhibitors can be used totreat patients with EGFR-TKI resistance, Heat shock protein90are rich innormal cells, account for1%-2%of total protein,Heat shock protein90ishighly expressed in malignant tumors, and participate in processes of cancerCells such as differentiation, proliferation,Metastasis and so on. Hsp90produce biological effects by combining with client proteins in cells，As weknow,there are more than200species client proteins of HSP90, most of themplayed an important role in cell signaling, including EGFR，HER2，etc.Studies have shown that: HSP90inhibition in cell, Will bring us multi-channelanti-tumor effects. At present, a variety of HSP90inhibitors have enteredclinical trials, and showing good anti-neoplastic effects in many solidmalignancies. HSP90inhibitors may be the durgs which could be used for thetreatment of patients with EGFR-TKI drug-resistant. Statistics show thatChina’s different regions and ethnic differences also exist EGFR mutations.However, with the EGFR-TKI applications, drug discovery will appear sooneror later in patients resistant to medication had no therapeutic effect, thuslimiting the EGFR-TKI in clinic. Therefore, seek EGFR-TKI resistancemechanisms and solutions become the hotspot. HSP90inhibitors are anothertarget for tumor therapy drugs currently HSP90inhibitors have been applied inclinical trials in the treatment of NSCLC, adenocarcinoma of the lung found inpatients resistant to EGFR-TKI also have a therapeutic effect. In an HSP90inhibitor therapy in patients with EGFR-TKI Phase Ⅱ clinical trial foundthat, HSP90inhibitors for EGFR mutations in lung cancer patients with higher efficiency.Studies suggest that:EGFR mutations and high expression of HSP90arethe preconditions of using EGFR-TKI and HSP90inhibitors.We do not knowwhether there was an association between EGFR-TKI and HSP90inhibitors,or there are some relationshios EGFR mutations and the expression of HSP90α.there are not too many reports on them.Objective:1Collect clinical data of patients, who past-line tested by EGFRmutations in lung adenocarcinoma analysis and explore the relationshipsbetween EGFR mutations and clinical features.2Test the expression of HSP90α in NSCLC, explore the differencesexpression rates and expression level in lung adenocarcinoma and in lungSquamous cell carcinoma, collection all the linical data of patients, Statisticaland analysis the data，and find the relationships between the expression ofHSP90in NSCLC and the clinical characteristics. We also counted the data ofEGFR mutations in112lung adenocarcinoma patients and analyzed thecorrelation between EGFR gene mutation and clinical factors.Method: All the cases specimens were selected from January2009toDecember2013period, the Fourth Hospital of Hebei Medical University,treated by surgery, biopsy or bronchial biopsy confirmed, and withoutradiotherapy and chemotherapy treatment of112cases of lungadenocarcinoma(71cases treated by surgical41patients with non-surgicaltreatment), and35cases of squamous cell carcinoma were treated bysurgical.All the112cases of lung cancer patients were EGFR mutationdetection (Fourth Hospital of Hebei Medical University, MEL method,detection sites: outside exon18,19,21);All patients TNM staging standardreference2009(IASLC/UICC) International Lung Cancer Staging (7th)1All112cases specimens were random selected from the4th Hospital ofHebei Medical University，and tested EGFR mutations by MEL method inpathology department. Collected all of the patient’s pathology and clinical data,Explore the situation of EGFR mutations in lung adenocarcinoma. 2Detect the expression of HSP90α in pathology of106NSCLC by SPimmunohistochemical method, explore the differences expression rates andexpression level in lung adenocarcinoma and in lung Squamous cellcarcinoma, collection all the linical data of patients, Statistical and analysis thedata，and find the relationships between the expression of HSP90in NSCLCand the clinical characteristics. We also counted the data of EGFR mutationsin112lung adenocarcinoma patients and analyzed the correlation betweenEGFR gene mutation and clinical factors.All specimens were graded by Semi-quantitative method forimmunohistochemical results, and take5pictures of each specimen with,useImagepro-Plus6.0image processing software for quantitative analysis. Theaverage gray value of5images, is the result for the quantitative analysis.Using Chi-square test and nonparametric rank sum test to process data,Analysis correlation between EGFR mutation in and the expression of HSP90Alpha in of lung adenocarcinoma. Collect clinical data of106patients andanalysis the relationships between the expression of HSP90α in NSCLCwith clinical factors.Result:1Relationships between the EGFR mutations in lung adenocarcinoma andclinical characteristicsAmong112cases of patients who had tested EGFR mutations,60caseswith EGFR mutations, mutation rate was53.6%(60/112), mutation rate inmale was40(26/65), and female72.3%(34/47),Chi-square test P=0.01，Therates of EGFR mutations in female are significantly higher than the rates inmale.EGFR mutation rate in smoking group was58.7%(54/92),rates innon-smoking was30.0%(6/20), chi-square test shown: P<0.05, EGFRmutations rates in non-smoking group was significantly higher than smokinggroup.Further statistical analysis reveal that there were no significantdifferences of the mutation rates in different ages and Clinical stages.EGFR mutations rates with exons18was8.3%(5/60), exons19was55%(33/60), exons21was36.7%(22/60);in males，exons18,exons19and exons21mutations rates were7.7%,57.7%,34.6%, and in females the rateswere8.8%,53.0%,38.2%, Chi-square test shown that there were nodifferences between them.2Expression of heat shock protein90in non-small cell lung cancerPositive expression rates of HSP90in lung adenocarcinoma was83.1%(59/71)and expression level was0.0250±0.0133；the rates in Squamouscell lung carcinoma was88.5%(31/35)and expression level was0.0263±0.0091;the positive expression rates of HSP90α in adenocarcinoma andsquamous cell carcinoma，Chi-square test shows P=0.459, non-parametricrank test P=0.389of analytical results. Tips that in lung adenocarcinoma andsquamous tissues, HSP90α positive expression rate and level no statisticaldifference.3Expression of heat shock protein90in non-small cell lung cancer and therelationships with clinical factors.3.1The Positive rate of HSP90α in stage I、II NSCLC was79.7%(63/79),expression level was0.0196±0.0066; and in stage III、IV NSCLC rates was100%(27/27), expression level was0385±0.0142. Chi-square test P=0.026,non-parametric rank test P=0.000, Tips：between stage I, II with III, IV theexpression rates and levels have significantly differences.3.2In N+group the positive expression rates of HSP90α was94%(47/50),expression level was0.0289±0.0105, and in N0was76.7%(43/56),expression level was0.0208±0.0114, Statistical analysis results：Chi-squaretest P=0.013, non-parametric rank test P=0.000. Tips：between N+and N0theexpression rates and levels have significantly differences.3.3Analyze the expressions HSP90α in NSCLC with different clinical factorsRespectively, such as Gender, age, smoking, tumor size pathological type andso on.Statistical analysis shown that there no correlations between them.Conclusion:1EGFR mutations rates in lung adenocarcinoma53.6%, and female,non-smoking patients mutations rate were Significantly higher than the male,smokers. Smoking and gender are the important factors which will have impact on EGFR mutations.2EGFR mutations in lung adenocarcinoma most concentrated on Exon19,21, and there was no significant correlation between mutations rate andgender.3HSP90α highly expressed in lung adenocarcinoma, there are nocorrelations between HSP90expression,and EGFR mutations has nosignificant effect on the expression of HSP90α.4HSP90α was highly expressed in non-small cell lung,TNM stage andlymph node metastasis were the factors which effect the expression rates andexpression levels of HSP90α，The later clinical staging and the more lymphnode metastasis, positive expression rates and levels of HSP90α will behigher.There relationships between gender, age, smoking, tumor sizepathological with the positive expression rates and levels of HSP90α...