Expressions And Clinical Significances Of EGFR/K-RAS And Mismatch Repair In Non-small Cell Lung Cancer

Objective: Lung cancer is one of the most common fatal disease in our countryand even all over the world. Non-small cell lung cancer (NSCLC) accounts forapproximately75%-85%of lung cancer. Surgical resection is the most commontreatment for the suffers, followed by chemotherapy and radiotherapy. However, mostof suffers lost the opportunity to receive the optimal treatment when the disease wasdiagnosed. Therefore, the mortality of the disease has the tendency to increase recently.In order to improve suffer’s quality of life, clinicians are demanded to discover,diagnose, and treat the disease as early as possible, which depend on well undestandingthe pathogenesis of the cancer. EGFR and K-RAS transduction system is a major signalpathway involved in cell growh and proliferation. It has been shown that developmentand progression of NSCLC as other malignancies are induced by the abnormalactivation of these proteins, which may be associated with the dysfunction ofintracellular mismatch repair (MMR) system. The function of MMR, which have beenformed during evolutionary process, is to repair gene damages during the process ofDNA replication. hMLH1and hMSH2, the most important proteins in MMR system,participate in repairing the damages and therefore maintaining genomic stability.Dysfunction of the two proteins can lead to accumulation of damages in genomeproduced by mismatch, which induce normal cell to transform malignantly. In order toinvestigate the reason of abnormal expressions of EGFR/K-RAS protein in thecarcinogenesis of NSCLC，we detected the expressions of EGFR, K-RAS, hMLH1and hMSH2proteins, and then analyzed the relationship of EGFR/K-RAS proteins tohMLH1/hMSH2proteins.Methods: The immunohistochemistry was used to detect protein expressions ofEGFR, K-RAS, hMLH1and hMSH2in110samples of NSCLC and35theirsurrounding tissues, and the Chi-square test and Fisher’s cxact test were used to analyze their correlations with clinicopathological agents (gender, age, smoking history, lymphnode metastasis, histological type, differentiation), especially the relationship ofEGFR/K-RAS protein expressions to hMLH1/hMSH2protein expressions.Results: The positive expression rate of EGFR protein in NSCLC was lower thanthat in surrounding tissues (46.4%vs51.4%, P>0.05). In NSCLC, no significantrelationship was found between protein expression and patient clinicopathologicalagents (P>0.05). The positive expression rate of K-RAS protein in NSCLC was higherthan that in surrounding tissues (39.1%vs28.6%, P>0.05). In NSCLC, no significantrelationship was found between protein expression and patient clinicopathologicalagents (P>0.05). The positive expression rate of hMLH1protein in NSCLC wassignificantly higher than that in surrounding tissues (54.5%vs14.3%, P<0.05). InNSCLC, the positive expression rate of hMLH1protein in the cancer tissues withoutlymph node metastasis was significantly higher than that with lymph node metastasis(64.9%vs43.4%, P<0.05); the positive expression rate of hMLH1protein in well andmoderately differentiated adenocarcinoma was significantly higher than that inbronchioalveolar carcinoma (65.1%vs0%, P<0.05); but no significant relationship wasfound between protein expression and other clinicopathological agents (P>0.05). Thepositive expression rate of hMSH2protein in NSCLC was significantly higher than thatin surrounding tissues (55.5%vs17.1%, P<0.05). In NSCLC, no significantrelationship was found between protein expression and patient clinicopathologicalagents (P>0.05).The expression of EGFR protein showed positive relation to those of K-RASprotein (P=0.017, r=0.227) and hMLH1protein (P=0.000, r=0.336), but that of hMSH2protein (P=0.915, r=-0.01); the expression of EGFR protein was positively related toco-expression of hMLH1/hMSH2proteins (P=0.030, r=0.207). The expression ofK-RAS protein did not show relation to those of hMLH1protein (P=0.167, r=0.133)and hMSH2protein (P=0.952, r=0.006); the expression of K-RAS protein was notrelated to co-expression of hMLH1/hMSH2proteins (P=0.152, r=0.137).Conclusion：1. hMLH1and hMSH2protein expressions were up-regulated inNSCLC, and detection of these protein expressions in lung tissues may be helpful forthe early diagnosis of NSCLC.2. NSCLC with down-regulated hMLH1protein expression had high potentialability to metastase to lymph node, so detection of its expression could be used toevaluate the feasibility of lymph node metastasis in NSCLC. 3. Up-regulation of K-RAS protein in NSCLC might be induced by theoverexpression of EGFR protein.4. The finding of overexpression of EGFR protein accompanied withoverexpression of mismatch repair protein in NSCLC indicated that overexpression ofEGFR protein might be induced by the mismatch during the process of DNAreplication.