Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells.

Autor:	Simbolo M; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Silvestris N; Medical Oncology Unit, Department of Human Pathology 'G. Barresi', University of Messina, Messina, Italy., Malleo G; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Mafficini A; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Maggino L; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Cocomazzi A; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Veghini L; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Mombello A; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Pezzini F; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Sereni E; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Martelli FM; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Gkountakos A; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Ciaparrone C; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Piredda ML; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Ingravallo G; Department of Emergency and Transplantation, Pathology Section, University of Bari Medical School, Bari, Italy., Paolino G; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Nappo F; Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Rapposelli IG; Medical Oncology Unit, IRST IRCCS, Meldola, Italy., Frassinetti L; Medical Oncology Unit, IRST IRCCS, Meldola, Italy., Saragoni L; Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni Hospital, Forlì, Italy., Lonardi S; Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Pea A; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Paiella S; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Fassan M; Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, and Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy., Brunetti O; IRCCS Istituto Tumori 'Giovanni Paolo II' of Bari, Vari, Italy., Cingarlini S; Department of Medicine, Section of Oncology, University and Hospital Trust of Verona, Verona, Italy., Salvia R; Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy., Milella M; Department of Medicine, Section of Oncology, University and Hospital Trust of Verona, Verona, Italy., Corbo V; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Lawlor RT; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Scarpa A; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy., Luchini C; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. Electronic address: claudio.luchini@univr.it.
Jazyk:	angličtina
Zdroj:	Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc [Mod Pathol] 2023 Sep; Vol. 36 (9), pp. 100251. Date of Electronic Publication: 2023 Jun 22.
DOI:	10.1016/j.modpat.2023.100251
Abstrakt:	Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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