Identification of biomarkers for molecular diagnosis of pancreatic ductal adenocarcinoma by high-resolution analysis of the transcriptome and exome

Abstract

Pancreatic cancer is one of the most lethal neoplasms and only 5% of affected individuals survive for more than five years after diagnosis. This is due to limitations to detect the disease in early stages and to the absence of effective therapeutic options. Ductal adenocarcinoma (PDAC) is the most prevalent pancreatic neoplasia, extremely aggressive and the only curative treatment available is the surgical removal of the tumor if detected at the early stages of the disease. Pancreatic cystic tumors may progress to invasive adenocarcinoma and currently there are no markers to safely predict their clinical evolution. To improve the treatment of these neoplasias it is vital to identify novel biomarkers for early diagnosis or to determine the risk of cystic lesions to develop into invasive tumors. In this proposal we will establish an analytical platform to identify alterations in RNA expression (transcriptome) or DNA sequence (exome) by high throughput sequencing of RNA/DNA from clinical samples of pancreatic tumors. An original aspect of the proposal will be the analysis of polyadenylated and nonpolyadenylated long noncoding RNAs expressed in samples of PDAC, premalignant lesions and nontumor pancreatic tissues. Another innovation will be the employment of pancreatic tumor biopsies collected by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), a minimally invasive method, to detect somatic alterations in the exome. We will also investigate the diagnostic potential of RNAs isolated from the plasma and the cystic fluid from patients with pancreatic cystic tumors. Integrated data analyses will allow the identification of genes, molecular pathways and functional modules preferentially affected by transcriptional or somatic alterations during malignant transformation and progression of pancreatic tumors. Differentially expressed RNAs and somatic mutations with potential diagnostic or clinical relevance will be selected and evaluated in an independent panel of patient samples. (AU)