YAP 1 and its Mediators as Key Players in Pancreatic Ductal Adenocarcinoma (PDAC): An Investigation through Whole Exome Sequencin

Abstract

Pancreatic cancer (PC) is a highly pernicious malignancy with a very poor survival rate of >5 years in 10% of its cases and is reported to be 7th leading cause of death worldwide. It initiates in pancreatic ducts but in later stages metastasize to adjacent tissues. PDAC is the most prevalent type of PC involve in 90% of its cases. In progression of PDAC by PanIN formation, mutation of 4 driver genes including KRAS, CDKN2A, p53, and SMAD4 plays a significant role. Along with these driver genes, other genes are also altered in PDAC including YAP1, ZEB1, and BRCA 1/2. The main objective of this research is the genetic characterization of PDAC sample with aim to analyze the role of YAP1 and p53 in PDAC cases. Molecular profiling of both tumor and control samples was done through WES which provided data regarding variants. Later on, using various bioinformatics tools sequencing data was observed that shown 3 novel nc-RNA variants (87341661; T>C, 87341667; A>T, 87345180; G>C) of p53TG1 and 1 exonic reported variant of p53 gene. While, no variation have been observed in the exonic region of YAP1 gene. However, several SNPs and indels were reported in the intronic region of both genes. Furthermore, ClinPred, LRT, MutationTaster, and Mutation Assessor tools confirmed the novelty of 3 nc-RNA variants and damaging effect of 1 exonic variant of p53 gene. No results were obtained for these 3 nc-RNA variants from VEST4, SIFT, PROVEAN, and PolyPhen2 which further validate their novelty. No data regarding these 3 variants were available in the AvSNP150, Cosmic92, and ClinSig database which confirms the uniqueness of these variants but SNP ID (rs1137282) and Cosmic ID (ID=COSV52663748) was assigned to 1 exonic variant of p53 gene. These variations might have role in regulating their own genetic expression along with other genes causing PanINs formation through ADM leading to PDAC progression. In future, to validate this study transcriptomic analysis and molecular docking can be done that will further pave way to develop diagnostic marker that will help in early detection and treatment of PDAC. Keywords: Pancreatic Ductal Adenocarcinoma (PDAC), Yes-Associated Protein 1 (YAP-1), Pancreatic Intraepithelial Neoplasia (PanIN), Whole Exome Sequencing (WES), long non-coding RNA (lnc-RNA), p53 Target Gene 1 (p53TG1).