A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients
Abstract 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...
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doaj-e23c79dfd1eb48aaa7793cdf3bab7cd12020-11-25T02:47:09ZengBMCMolecular Medicine1076-15511528-36582020-06-0126112110.1186/s10020-020-00183-1A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patientsGourab Saha0Richa Singh1Argha Mandal2Subrata Das3Esita Chattopadhyay4Prasun Panja5Paromita Roy6Navonil DeSarkar7Sumit Gulati8Supriyo Ghatak9Shibajyoti Ghosh10Sudeep Banerjee11Bidyut Roy12Saurabh Ghosh13Dipankar Chaudhuri14Neeraj Arora15Nidhan K. Biswas16Nilabja Sikdar17Human Genetics Unit, Indian Statistical InstituteHuman Genetics Unit, Indian Statistical InstituteDepartment of Biotechnology, Heritage Institute of TechnologyNational Institute of Biomedical GenomicsHuman Genetics Unit, Indian Statistical InstituteHuman Genetics Unit, Indian Statistical InstituteDepartment of Pathology & Department of Gastrointestinal Surgery, Tata Medical CenterDivision of Medical Oncology, Department of Medicine, University of WashingtonDepartment of Surgical Gastroenterology, Calcutta Medical Research InstituteDepartment of Surgical Gastroenterology, Calcutta Medical Research InstituteDepartment of General Surgery, Medical College and HospitalDepartment of Pathology & Department of Gastrointestinal Surgery, Tata Medical CenterHuman Genetics Unit, Indian Statistical InstituteHuman Genetics Unit, Indian Statistical InstituteDepartment of Biotechnology, Heritage Institute of TechnologyDepartment of Pathology & Department of Gastrointestinal Surgery, Tata Medical CenterNational Institute of Biomedical GenomicsHuman Genetics Unit, Indian Statistical InstituteAbstract 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.http://link.springer.com/article/10.1186/s10020-020-00183-1Pancreatic ductal adenocarcinomaPeriampullary adenocarcinomaNovel somatic hotspot mutationFrequently mutated genesNext generation sequencing |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gourab Saha Richa Singh Argha Mandal Subrata Das Esita Chattopadhyay Prasun Panja Paromita Roy Navonil DeSarkar Sumit Gulati Supriyo Ghatak Shibajyoti Ghosh Sudeep Banerjee Bidyut Roy Saurabh Ghosh Dipankar Chaudhuri Neeraj Arora Nidhan K. Biswas Nilabja Sikdar |
spellingShingle |
Gourab Saha Richa Singh Argha Mandal Subrata Das Esita Chattopadhyay Prasun Panja Paromita Roy Navonil DeSarkar Sumit Gulati Supriyo Ghatak Shibajyoti Ghosh Sudeep Banerjee Bidyut Roy Saurabh Ghosh Dipankar Chaudhuri Neeraj Arora Nidhan K. Biswas Nilabja Sikdar A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients Molecular Medicine Pancreatic ductal adenocarcinoma Periampullary adenocarcinoma Novel somatic hotspot mutation Frequently mutated genes Next generation sequencing |
author_facet |
Gourab Saha Richa Singh Argha Mandal Subrata Das Esita Chattopadhyay Prasun Panja Paromita Roy Navonil DeSarkar Sumit Gulati Supriyo Ghatak Shibajyoti Ghosh Sudeep Banerjee Bidyut Roy Saurabh Ghosh Dipankar Chaudhuri Neeraj Arora Nidhan K. Biswas Nilabja Sikdar |
author_sort |
Gourab Saha |
title |
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
title_short |
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
title_full |
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
title_fullStr |
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
title_full_unstemmed |
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
title_sort |
novel hotspot and rare somatic mutation p.a138v, at tp53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients |
publisher |
BMC |
series |
Molecular Medicine |
issn |
1076-1551 1528-3658 |
publishDate |
2020-06-01 |
description |
Abstract 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. |
topic |
Pancreatic ductal adenocarcinoma Periampullary adenocarcinoma Novel somatic hotspot mutation Frequently mutated genes Next generation sequencing |
url |
http://link.springer.com/article/10.1186/s10020-020-00183-1 |
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