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Background  Pancreatic Ductal Adenocarcinoma (PDAC) is a cancer of the exocrine pancreas and 5-year survival rates remain constant at 7%. Along with PDAC, Periampullary Adenocarcinoma (PAC) accounts for 0.5–2% of all gastrointestinal malignancies. Genomic observations were well concluded for PDAC and PACs in western countries but no reports are available from India till now.    Methods  Targeted Next Generation Sequencing were performed in 8 (5 PDAC and 3 PAC) tumour normal pairs, using a panel of 412 cancer related genes. Primary findings were replicated in 85 tumour samples (31 PDAC and 54 PAC) using the Sanger sequencing. Mutations were also validated by ASPCR, RFLP, and Ion Torrent sequencing. IHC along with molecular dynamics and docking studies were performed for the  p.A138V  mutant of  TP53 . Key polymorphisms at  TP53  and its associated genes were genotyped by PCR-RFLP method and association with somatic mutations were evaluated. All survival analysis was done using the Kaplan-Meier survival method which revealed that the survival rates varied significantly depending on the somatic mutations the patients harboured.    Results  Among the total 114 detected somatic mutations,  TP53  was the most frequently mutated (41%) gene, followed by  KRAS ,  SMAD4 ,  CTNNB1 , and  ERBB3.  We identified a novel hotspot  TP53  mutation ( p.A138V , in 17% of all patients). Low frequency of  KRAS  mutation (33%) was detected in these samples compared to patients from Western counties. Molecular Dynamics (MD) simulation and DNA-protein docking analysis predicted  p.A138V  to have oncogenic characteristics. Patients with  p.A138V  mutation showed poorer overall survival ( p = 0.01 ). So, our finding highlights elevated prevalence of the p53 p.A138V  somatic mutation in PDAC and pancreatobiliary PAC patients.    Conclusion  Detection of  p.A138V  somatic variant in  TP53  might serve as a prognostic marker to classify patients. It might also have a role in determining treatment regimes. In addition, low frequency of  KRAS  hotspot mutation mostly in Indian PDAC patient cohort indicates presence of other early drivers in malignant transformation.

molecular medicine

A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients