| BackgroundLung cancer and esophageal cancer are both the most common malignant tumors all over the world. Lung cancer, which ranks first in order of occurrence and mortality in the world, brought in more than1,000,000cancer-related deaths annually. In2010, lung cancer and esophageal cancer rank first and fifth in order of occurrence in China. There are two main pathologic subtypes in non-small cell lung cancer(NSCLC): adenocarcinoma ang squamous cell carcinoma(SCC). Squamous cell carcinoma consists of more than30%in NSCLC though incidence of adenocarcinoma is consistently increasing these years. Despite of the significant benefit to patients with adenocarcinoma, prognosis of patients with squamous cell carcinoma is still dismal. The same situation also exists in patients with esophageal squamous cell carcinoma. Esophageal cancer pathology type mainly includes esophageal squamous cell carcinoma(ESCC) and esophageal adenocarcinoma(EADC). Esophageal cancer also has the characteristic of regional distribution, the most common pathologic type of esophageal cancer in Asian countries is squamous cell carcinoma, and China is one of the countries with high incidence of esophageal cancer. About90%of esophageal cancer in our country is squamous cell carcinoma. Along with the development of the social science, the treatment of esophageal cancer has developed into an integrated treatment model with primary surgery and combined radiotherapy and chemotherapy. In our country, surgery is still the main treatment of resectable esophageal cancer, in recent years, along with the improvement of the diagnosis and operation technique, with the application of preoperative neoadjuvant chemotherapy, coupled with postoperative chemotherapy and radiotherapy, the life quality of patients has been improved to a certain extent. But the effect of treatment of esophageal carcinoma is still not satisfactory, the overall5-year survival rate of ESCC is only20%-30%. SCC presents an important feld where novel targeted therapeutic agents are eagerly awaited in LSCC and ESCC both.Although recognition of molecular subtypes in SCC lags behind what is known in other tumors, a group of RTK alterations with remarkable biological signifcance have been described as more and more attention is focused on this topic. FGFR1is a member of the FGFR family of receptor tyrosine kinases; activation leads to downstream signaling via the phosphatidylinositol3-kinase/v-akt murine thymoma viral oncogene homolog1(PI3K/AKT)/reticular activating system/mitogen activated protein kinase(RAS/MAPK) pathways, which are central to growth, survival migration, and angiogenesis in many types of cancer. Dysregulation of FGFR signaling has been described in multiple cancers, with amplifcation, translocation, and point mutations being described in a broad range of tumor types including breast, prostate, myeloma, sarcoma, bladder, and endometrial cancers, among others.In lung cancer, FGFR1amplifcation is found in approximately20%of squamous cell cancers, but rarely in adenocarcinoma. Inhibition of FGFR1in amplifed cell lines and in mouse models with FGFR1-amplifed engrafted tumors showed growth inhibition and induced apoptosis. Multiple FGFR inhibitors are in development; many of these are multitargeted tyrosine kinase inhibitors with activity against other targets in addition to FGFR1. In esophageal cancer, there has been few studies that focused on FGFR1. But chromesome segment8pl1-12was actually found amplified using large-scale single nucleotide polymorphismarrays where FGFR1gene located. Several manuscripts have reported similar results with different sample sizes. Other than the association with ESCC, little is known about clinical or demographic correlates of FGFR1amplifcation.So far, there are no reports about whether FGFR1gene amplification is amplificated in LSCC and ESCC and its relationship with clinicopathological features in China. There have already been some reports about FGFR1gene amplification and LSCC, but the research results are not consistent, some results were even opposite completely. And whether there is correlation between FGFR1gene amplification and prognosis in resectable LSCC and ESCC is still not clear. The aim of this study was to detect the frequency of FGFR1gene amplification in LSCCand ESCC, and further investigate the correlation between FGFR1gene amplification status with biological behavior and prognosis of LSCC and ESCC. In this study, fluorescence in situ hybridization (FISH) assay was used to detect FGFR1gene amplification status. The findings of this study will provide theoretical bases for the further exploring of pathogenesis of LSCC and ESCC and searching for the ideal target for gene therapy of these two kinds of cancer.Part one:FGFR1gene amplification status in lung squantous cell carcinoma and the relationship with clinicopathological characteristicsObjective:The occurrence and the development of lung cancer were complex pathological processes involved multiple factors and steps, the aim of this study was to detect the frequency of FGFR1gene amplification in LSCC tissues and investigate the relationship between FGFR1gene amplification and the clinicopathological characteristics, further explore the possible mechanism of LSCC.Methods:From January2008to January2011, we collected162specimens of LSCC patients underwent the complete resection of tumor in Department of thoracic surgery provincial hospital affiliated to Shandong University, including142cases of LSCC and20cases adjacent normal lung tissues selected randomly. The frequency of FGFR1gene amplification was detected by FISH assay. SPSS19.0software package was used to analyze the results. The clinicopathological characteristics and experimental results were included into the database. Enumeration data was calculated by positive rate, and compared by chi-square test; measurement data was represent with average±standard deviation, the difference of groups were compared by t-test or F-test, and SNK test for comparing the difference of pairwise groups. P<0.05was considered statistically significant.Results:The frequency of FGFR1gene amplification in LSCC tissues was16.9%which was significantly higher than in adjacent normal lung tissues (P<0.05). There was FGFR1gene copy number gain in adjacent lung tissues of2patients who were heavy smokers. FGFR1gene amplification status was not correlated with sex(P>0.05). FGFR1gene amplification status was not correlated with age(>60and<60)(P>0.05). FGFR1gene amplification status was not correlated with pT, pN and pTNM stage(P>0.05). There was correlation between FGFR1gene amplification and smoking status in LSCC(P<0.05).Conclusion:FGFR1gene amplification status was correlated with smoking status regardless of sex, age, tumor diameter, pT, pN and pTNM. The fact that there was correlation between FGFR1gene amplification and smoking status and FGFR1gene copy number gain in adjacent lung tissues of2patients who were heavy smokers may suggest that some component in cigarette may lead to FGFR1gene amplification in LSCC. FGFR1gene amplification may provide a meaningful therapeutic target. Part two:FGFRl gene amplification status in esophageal squamous cell carcinoma and the relationship with clinicopathological characteristicsObjective:The occurrence and the development of esophageal cancer were complex pathological processes involved multiple factors, the aim of this study was to detect the frequency of FGFR1gene amplification in ESCC tissues and investigate the relationship between frequency of FGFR1gene amplification and the clinicopathological characteristics, further explore the possible mechanism of ESCC.Methods:From January2010to January2011,82patients with ESCC underwent the complete resection of esophageal carcinoma in the Department of thoracic surgery, provincial hospital affiliated to Shandong University were included into this study, including82cases of ESCC and20cases adjacent normal esophageal tissue selected randomly. The frequency of FGFR1gene amplification was detected by FISH assay. Follow-up was completed in all82patients. SPSS19.0software package for statistical analysis. The clinicopathological characteristics and experimental results were included into the database. Enumeration data was calculated by positive rate, and compared by chi-square test; measurement data was represent with average±standard deviation, the difference of groups were compared by t-test or F-test, and SNK test for comparing the difference of pairwise groups. P<0.05was considered statistically significant.Results:The frequency of FGFR1gene amplification in ESCC tissue was15.8%which was significantly higher than in adjacent normal esophageal tissues (P<0.05). FGFR1gene amplification status was not correlated with sex(P>0.05). FGFR1gene amplification status was not correlated with age(>60and<60)(P>0.05). FGFR1gene amplification status was not correlated with pT and pTNM stage(P>0.05). There was correlation between FGFR1gene amplification and lymphnode metastases status in ESCC(.P<0.05). There was no correlation between FGFR1gene amplification and smoking status in ESCC(P>0.05). There was no correlation between FGFR1gene amplification and alcohol intake status in ESCC(P>0.05).Conclusion:FGFR1gene amplification status was not correlated with sex, age, tumor diameter, pT and pTNM. FGFR1gene amplification status was correlated with lymphnode metastases. The fact that there was higher frequency of FGFR1gene amplification in tumor tissue of patients who had lymphnode metastases may suggest FGFR1gene amplification may play a role in lymphatic spread. FGFR1gene amplification may provide a meaningful therapeutic target for ESCC. Part three:The relationship between FGFR1gene amplification and the prognosis of lung and esophageal squamous cell carcinomaObjective:Lung cancer and esophageal cancer were both malignant tumors with high incidence, mortality and poor prognosis. We always hope to find some biological indicators which could predict the prognosis of esophageal carcinoma. This study aimed to investigate the relationship between FGFR1gene amplification and prognosis of LSCC and ESCC.Methods:142patients with LSCC who underwent the complete resection of lung carcinoma from January2008to January2011and82patients with ESCC who underwent the complete resection of esophageal cancer from January2010to January2011, in the Department of thoracic surgery, provincial hospital affiliated to Shandong University were included into this study. The frequency of FGFR1gene amplification in LSCC and ESCC tissue was detected by FISH assay. Follow-up was completed in the all224patients. SPSS19.0software package for statistical analysis, the clinicopathological characteristics and FISH results were included into the database. Kaplan-Meier method was used to calculate the survival rate, and the difference of survival rates were compared by Log-rank test. Cox-regression analysis was applied to determine the independent risk factors of ESCC prognosis. P<0.05was considered statistically significant.Results:The3-year survival rate of142postoperative patients with LSCC in this study was49.3%. The3-year survival rate of82postoperative patients with ESCC in this study was53.7%. In univariate analysis, the3-year survival rate of the patients with LSCC after surgery was significantly correlated with lymph node metastases and pTNM stage, while the rate of the patients with ESCC after surgery was significantly correlated with depth of invasion(pT), lymph node metastasis, pTNM stage. The3-years survival rate of patients with lymph node metastases and different TNM stage were difference significantly in LSCC(.P<0.05, P<0.05); The3-years survival rate of patients with different invasion depth(pT), lymphnode metastases and TNM stage were difference significantly in ESCC(P<0.05, P<0.05, P<0.05); The3-years survival rate of patients with lymphnode metastases was significantly lower than patients without lymph node metastasis in both LSCCand ESCC(P<0.05). The3-years survival rate of patients with FGFR1gene amplification was significantly lower than patients without amplification in LSCC(P<0.05). Cox-regression multivariate analysis showed that FGFR1gene amplification, lymphnode metastases, pTNM stage were independent risk factors of3-year survival rate of LSCC while the depth of tumor invasion(pT) and lymphnode metastases were independent risk factors of3-year survival rate of ESCC.Conclusion:In LSCC, FGFR1gene amplification, lymphnode metastases, pTNM stage were independent risk factors of3-year survival rate. In ESCC, FGFR1gene amplification, depth of tumor invasion(pT) and lymphnode metastases were correlated with3-year survival rate of patients after surgery. Depth of tumor invasion(pT) and lymphnode metastases were independent risk factors.of3-year survival rate. |
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