Genomic mapping of epithelial-to-mesenchymal transition in lung carcinomas: the impact of transition in invasion and tumor progression

• Grant number: 13/10113-7
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): March 01, 2014
• Effective date (End): June 30, 2018
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Vera Luiza Capelozzi
• Grantee: Tabatha Gutierrez Prieto Martins Rocha
• Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Because of restricted treatment options of lung cancer patients, the routine of the pathologist has been to differentiate smal cell from non-small cell carcinoma and stage resections. The new IASLC/ATS/ERS classification brings perspective to systematize lung adenocarcinoma through radiology, pathology, pathobiology, molecular pathogenesis and targeted therapeutics. It remains a histopathological classification that now includes special stains and immunohistochemistry panels with the purpose in integrating histology into a diagnostic category. Another major priority of the classification is to provide diagnosis in small samples that guide further testing and therapies, mainly the distinction of adenocarcinoma from other subtypes, specially squamous. It emphasizes to the pathologist that the samples must be taken in order not only to the histological diagnosis, but also to preserve the tissue for molecular studies. The CAP/IASLC/AMP lung cancer biomarkers guidelines confirmed for targeted therapy in lung cancer: activating mutations of EGFR gene which are more prevalent in patients who respond to tyrosine kinase inhibitors: gefitinib or iressa and erlotinib or tarceva, and the presence of ALK fusion genes which predicts response to crizotinib. In the present work our objective is profiling primary squamous cell lung carcinomas, adenocarcinomas, neuroendocrine carcinomas and large cell carcinomas from 100 patients who underwent to surgical resection for EMT genes using RT2 prolifer array (qPCR). Cluster analysis will be composed by statistical analysis and correlated to tumor stage, histological types and overall patient survival. The high-risk cluster will be associated to up or down-regulation of EMT genes. Cox proportional hazard models will identify the optimal set of prognostic mRNA transcripts using a 5-fold cross-validation procedure. Quantitative reverse transcription-PCR will used to validate individual gene candidates. The signature will be tested according to their independent set in histological types to achieve their ROC curve specificity and sensitivity with the overall predictive accuracy. Kaplan-Meier analysis will stratify high-risk and low-risk patients according to log-rank P value; Hazard Ratio (HR), and confidence interval (95% CI). Finally, we will combine the histological types classifier with our previously identified histological subtypes prognostic signature to determine the predictive accuracy of combined classifier. This prognostic signature could be used to identify patients with early-stage high-risk lung carcinomas who might benefit from adjuvant therapy following surgery. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

ROCHA, Tabatha Gutierrez Prieto Martins. Evaluation of genes involved in the epithelial-mesenchymal transition and its relation to tumor progression and invasion in lung cancer. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina São Paulo.