Long-term survivors of pancreatic adenocarcinoma show low rates of genetic alterations in KRAS, TP53 and SMAD4

Article type: Research Article

Authors: Masetti, Michele^{a; 1} | Acquaviva, Giorgia^{b; 1} | Visani, Michela^b | Tallini, Giovanni^{b; *} | Fornelli, Adele^c | Ragazzi, Moira^d | Vasuri, Francesco^e | Grifoni, Daniela^f | Di Giacomo, Simone^f | Fiorino, Sirio^g | Lombardi, Raffaele^a | Tuminati, David^a | Ravaioli, Matteo^h | Fabbri, Carloⁱ | Bacchi-Reggiani, Maria Letizia^j | Pession, Annalisa^f | Jovine, Elio^{a; 2} | de Biase, Dario^{f; 2}

Affiliations: [a] Surgery Unit, Azienda USL-Maggiore Hospital, Bologna, Italy | [b] 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 | [c] Anatomic Pathology Unit, Azienda USL-Maggiore Hospital, Bologna, Italy | [d] Anatomic Pathology Unit, Arcispedale Santa Maria Nuova – IRCCS, Reggio Emilia, Italy | [e] Anatomic Pathology Unit, “F. Addarii” Institute of Oncology and Transplantation Pathology, S. Orsola-Malpighi University Hospital, Bologna, Italy | [f] Department of Pharmacy and Biotechnology (Dipartimento di Farmacia e Biotecnologie) – Molecular Diagnostic Unit, Azienda USL di Bologna, University of Bologna, Bologna, Italy | [g] Internal Medicine Unit, Maggiore Hospital, Bologna, Italy | [h] Department of General Surgery and Transplantation, St. Orsola-Malpighi University Hospital, Bologna, Italy | [i] Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Bologna, Italy | [j] Department of Medicine (Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale), Cardiology Unit, Policlinico S. Orsola-Malpighi, University of Bologna, Bologna, Italy

Correspondence: [*] Corresponding author: Tallini Giovanni, Scuola di Medicina e Chirurgia, Università di Bologna, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Anatomia Patologica, ASL Bologna, Via Altura 3, 40139 Bologna, Italy. Tel.: +39 051 6225757; Fax: +39 051 6225759; E-mail: [email protected]@ausl.bo.it.

Note: [1] Michele Masetti and Giorgia Acquaviva contributed equally to this work.

Note: [2] Elio Jovine and Dario de Biase share senior authorship.

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.

Keywords: Pancreatic adenocarcinoma, KRAS, TP53, SMAD4, mutation

DOI: 10.3233/CBM-170464

Journal: Cancer Biomarkers, vol. 21, no. 2, pp. 323-334, 2018