A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients. Mol Med 2020 Jun 17;26(1):59
Date
06/20/2020Pubmed ID
32552660Pubmed Central ID
PMC7302128DOI
10.1186/s10020-020-00183-1Scopus ID
2-s2.0-85086694366 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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 p53p.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.
Author List
Saha G, Singh R, Mandal A, Das S, Chattopadhyay E, Panja P, Roy P, DeSarkar N, Gulati S, Ghatak S, Ghosh S, Banerjee S, Roy B, Ghosh S, Chaudhuri D, Arora N, Biswas NK, Sikdar NAuthor
Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAmpulla of Vater
Biomarkers, Tumor
Carcinoma, Pancreatic Ductal
Female
Genotype
Germ-Line Mutation
Humans
Kaplan-Meier Estimate
Male
Mutation
Neoplasm Grading
Neoplasm Staging
Pancreatic Neoplasms
Prognosis
Tumor Suppressor Protein p53
