Investigating the Role of ZEB1 and YAP1 in Pancreatic Ductal Adenocarcinoma through Whole Exome Sequencing

Abstract

Pancreatic cancer is one of the deadliest among cancer types, ranked as seventh leading cause of cancer mortality. Pancreatic Ductal Adenocarcinoma (PDAC), the most lethal and common pancreatic malignancy with poor survival rate of <5 year and fourth leading cause of cancer related deaths worldwide. It develops in pancreatic ducts and rapidly metastasized to nearby organs including lungs and liver. Different mutations in driver genes including KRAS, Tp53, SMAD4, and CDKN2A have reported to be actively involved in poor prognosis of PDAC. This study aims to identify the role of ZEB1 and YAP1 in PDAC cases with the objective of genetic characterization in freshly resected tumor tissue samples matched with control through Whole Exome Sequencing. Analysis of sequencing data using bioinformatics tools, have presented a novel substitutive nucleotide variation (31309911-12; GG>TA) in ZEB1-AS1, while no variation have been observed in exonic region of YAP1 genes. However, multiple single nucleotide variations (SNVs) and indels were present in intronic and intergeneric regions of both genes that may held responsible for their upregulation and active role in promotion of tumorigenesis of PDAC. Furthermore, a novel SNV have been found in exonic region of SMAD4 (51058160; G>A), KRAS (51058160; G>A) and in p53 (7674945; G>A) while no variation have been observed in exonic region of CDKN2A. In silico studies using multiple tools including, SIFT, Polyphen2, PROVEAN, Mutation tester, CADD Raw and Clin Pred have confirmed the novelty of identified variants. Transcriptome analysis and molecular docking can further help to validate the results and pave the way to devise diagnostic marker for early detection and promising therapeutic approaches. Keywords: Pancreatic Ductal Adenocarcinoma (PDAC), Zinc finger E-box binding homeobox 1 (ZEB1), ZEB1 antisense 1 (ZEB1-AS1), Yes-Associated Protein 1 (YAP1), Whole Exome Sequencing (WES)