The Predictive Value Of Recurrence Of TTF-1,SPA, ERCC1and RRM1Protein Expression And EGFR Mutation In Ⅰ～ⅢResection Lung Adenocarcinoma Tiusse

Background and purposeIn Worldwide, lung cancer has become one of the highest morbidity and mortality of malignant tumors. Although surgery is the only treatment method to obtain long-term survival of the disease, most of patients would relapse after surgical treatment. So the recurrence is a major obstacle to get long-term survival. The mean of predicting recurrence is to find out patients with high risk, make sure these patients get adjuvant after surgery. The study of this field was major in detecting the gene mutation and the protein expression. The following molecules are research hotpots in recently years:EGFR gene mutation, TTF-1, SPA, ERCC1and RRM1get the expression.Thyroid transcription factor (TTF-1) is a nuclear transcription factor NKx-2family members, the use of TTF-1protein expression in the tissue to identification primary and metastatic lung cancer, lung adenocarcinoma and lung squamous carcinoma. There were a number of studies which prove that TTF-1expression is a favorable prognostic factor in NSCLC. Surfactant protein-A (SPA) was composed by the phospholipid and protein complexes, which role in reducing the alveolar surface tension. There was relationship between the absence of SPA and the prognosis of lung cancer. Epidermal growth factor receptor (EGFR) is a receptor including tyrosine kinase region, the activation of EGFR can promote tumor growth, for example:involved in cell proliferation, inhibition of angiogenesis, apoptosis, cell adhesion, metastasis and aggressivity. The patients who habor EGFR mutation will have a high effective rate after targeted drugs treatment. There was article which shows that early lung cancer with EGFR mutation postoperative recurrence frequency more than the local recurrence in the distance.ERCC1is the5’ endonuclease of the nucleotide excision repair complex. It is found in all tumor cells, and its level of expression varies widely. In patients with completely resected NSCLC who did not receive perioperative chemotherapy or radiation, ERCC1mRNA levels were prognostic of survival. At present, a number of clinical studies have confirmed ERCC1expression level can predict the sensitivity to platinum based chemotherapy in NSCLC patients. In recent years, there was still debated on the expression of ERCC1both at the level of protein or RNA to predict the outcome of NSCLC, especially these early NSCLC patients receiveding platinum based chemotherapy. Most of the research confirmed that the expression level ERCC1is a independent prognostic factor in postoperative NSCLC patients. RRM1is the gene that encodes the regulatory subunit of ribonucleotide reductase, and it is crucial for production of deoxynucleotides from nucleotides. RRM1is found in all tumor cells, and its level of expression varies widely over a continuous range. In patients with completely resected NSCLC who did not receive perioperative chemotherapy or radiation, RRM1mRNA levels were prognostic of survival. Patients whose tumors had high levels lived significantly longer than patients whose tumors had low levels.The ever study was about single factor, besides we had found that the relationship between EGFR mutation, TTF-1, SPA, ERCC and RRM1expression in past research. The purpose of this paper is to discuss these factors in the predictive value of postoperative recurrence of lung adenocarcinoma. Materials and methodsThere were112I～III stage cases of lung adenocarcinoma being Collected from January2010to December2011in henan province tumor hospital. These patients received surgical resection with being detected of EGFR mutations, with complete clinical and pathological and follow-up data confirmed, and these patients did not receive any preoperative treatment. The expression of TTF-1, SPA, ERCC1and RRM1protein were detected immunohistochemical. The statistical data were analyzed through SPSS17.0software package. The relationship between the expression of TTF-1, SPA, ERCC1and RRM1and EGFR mutation in tissue and the DFS of lung adenocarcinoma after resection by drawing the Kaplan-Meier curve, the difference was compared by log-rank. The difference limited to P<0.05is considered statistically significant.Result1The DFS of I-III resection lung adenocarcinomaThe media follow up time is20months, the rate of1-and3-year DFS were73.2%and56.7%respectively.44patients were confirmed recurrent, which included11cases with local recurrence and33patients with distance metastasis. The most common place of distance metastasis was bone (12), and then the brain (8), adrenalgland (3) and liver (2). The media DFS was25.4months.2The EGFR (19/21)mutation statue, TTF-1, SPA, ERCC1and RRM1expression in I-III lung adenocarcinoma tissue2.1The EGFR mutation statueThere were53patients who detected the EGFR gene mutation in112cases of I-III lung adenocarcinoma tissue, which accounted for47.3%. There were20cases with19exons deletion and33patients carrying21point mutations in the53lung adenocarcinoma. the proportion of EGFR mutations in women was more than men (56.9%vs.39.3%), and the proportion of it in non-smoking patients is higher than never-smoking cases (53.8%VS38.3%).It was more common in patients without lymph node metastasis than with lymph node metastasis (50.7%VS41.9%), and more than occurred in I period patients (56.6%VS39.0%), but the difference did not reach statistical significance.2.2The TTF-1and SPA expression in tissueOf the112I-III lung adenocarcinoma tissue, there was97cases with TTF-1positive expression, accounting for86.6%. The positive expression of TTF-1was common in women as well as non-smokers. A total of71cases was detected SPA positive expression, accounting for63.4%(71/112), there were no significant correlation SPA expression and clinical features in the tissue.2.3The ERCC1and RRM1expression in tissueThe proportion of ERCC1and RRM1-positive expression was44.6%(50/112) and43.8%(49/112), respectively. The difference between the expression of ERCC1and RRM1and the the clinical features did not research statistical significance.3The impact of these factors on the DFS in I～III lung adenocarcinoma tissue3.1The impact of EGFR mutation on the DFSThe mean DFS of patients with EGFR wild,19exon mutation and21exon mutation were23months,20.9months and28.1months (P=0.288).3.2The impact of TTF-1and SPA expression mutation on the DFSThe DFS in these patients with TTF-1positive expression was longer than the cases with TTF-1negative expression (26.2m VS17.2), DFS was significantly longer in lung adenocarcinoma with SPA positive expression compare with negative expression (28.6m VS18.8m).3.3The impact of ERCC1and RRM1expression on the DFS The mean DFS of ERCC1in patients with negative and positive expression were29.5m and18.5m, respectively, the difference was statistically significant (P=0.000). The mean DFS of patients with RRM1positive expression was26.9m,and the negative was21.4m, but the difference did not reachstatistically significant (P=0.173).Conclusion1. The DFS of I-III stage postoperative lung adenocarcinoma patients with21exon mutation was longer than patients with19exon mutation or wild.2. The DFS of I-III stage postoperative lung adenocarcinoma with TTF-1and SPA positive expression was longer than the cases with these maker negative.3. The DFS of I-III stage postoperative lung adenocarcinoma with ERCC1and RRM1negative expression was longer than the cases with these maker positive.