Michele Masetti1,1, Giorgia Acquaviva2,1, Michela Visani2, Giovanni Tallini2, Adele Fornelli3, Moira Ragazzi4, Francesco Vasuri5, Daniela Grifoni6, Simone Di Giacomo6, Sirio Fiorino7, Raffaele Lombardi1, David Tuminati1, Matteo Ravaioli8, Carlo Fabbri9, Maria Letizia Bacchi-Reggiani10, Annalisa Pession6, Elio Jovine1,2, Dario de Biase6,2. 1. Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy. 2. Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna School of Medicine, Bologna, Italy. 3. Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Bologna, Italy. 4. Anatomic Pathology Unit, Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy. 5. Anatomic Pathology Unit, "F. Addarii" Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy. 6. Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) - Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy. 7. Internal Medicine Unit, Maggiore Hospital, Bologna, Italy. 8. Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy. 9. Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Bologna, Italy. 10. Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Cardiology Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy.
Abstract
BACKGROUND: Pancreatic adenocarcinoma (PDAC) is one of the deadliest human malignancies. Although surgery is currently the only effective treatment for PDAC, most patients survive less than 20 months after tumor resection. OBJECTIVE: The primary goal was to investigate alterations in KRAS, TP53, SMAD4 and CDKN2A/p16 in tumors from patients with exceptionally long survival after surgery. METHODS: Tumors from 15 patients with PDAC that survived more than 55 months after surgery ("LS") were analyzed for KRAS, TP53, IDH1, NRAS and BRAF using next-generation sequencing. SMAD4 and CDKN2A/p16 was tested using immunohistochemistry. MGMT promoter methylation was investigated. RESULTS: Tumors from "LS" have a lower prevalence of KRAS and TP53 mutations and had more frequently SMAD4 retained expression, if compared with that of patients died within 24 months from surgery. The survival of patients with wild-type KRAS and TP53 tumors was more than twice longer than that of patients bearing KRAS and TP53 mutations (90.2 vs. 41.1 months). Patients with KRAS wild-type tumors and that retained SMAD4 expression had a survival twice longer than cases with alterations in both genes (83.8 vs. 36.7 months). Eleven tumors (39.3%) showed MGMT methylation. CONCLUSIONS: Our data indicate that absence of KRAS, TP53 and SMAD4 genetic alterations may identify a subset of pancreatic carcinomas with better outcome.
BACKGROUND:Pancreatic adenocarcinoma (PDAC) is one of the deadliest humanmalignancies. Although surgery is currently the only effective treatment for PDAC, most patients survive less than 20 months after tumor resection. OBJECTIVE: The primary goal was to investigate alterations in KRAS, TP53, SMAD4 and CDKN2A/p16 in tumors from patients with exceptionally long survival after surgery. METHODS:Tumors from 15 patients with PDAC that survived more than 55 months after surgery ("LS") were analyzed for KRAS, TP53, IDH1, NRAS and BRAF using next-generation sequencing. SMAD4 and CDKN2A/p16 was tested using immunohistochemistry. MGMT promoter methylation was investigated. RESULTS:Tumors from "LS" have a lower prevalence of KRAS and TP53 mutations and had more frequently SMAD4 retained expression, if compared with that of patients died within 24 months from surgery. The survival of patients with wild-type KRAS and TP53tumors was more than twice longer than that of patients bearing KRAS and TP53 mutations (90.2 vs. 41.1 months). Patients with KRAS wild-type tumors and that retained SMAD4 expression had a survival twice longer than cases with alterations in both genes (83.8 vs. 36.7 months). Eleven tumors (39.3%) showed MGMT methylation. CONCLUSIONS: Our data indicate that absence of KRAS, TP53 and SMAD4 genetic alterations may identify a subset of pancreatic carcinomas with better outcome.
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