title: Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas.
abstract: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS).
  
  
  
  Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm.
  
  
  
  Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression.
  
  
  
  We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas.
  
  
  
  Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.
authors.affiliation: *Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland †Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy ‡Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland §Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy ¶Departments of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland ||Departments of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland **ARC-Net applied research on cancer center, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pea
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Neda
authors.initials: N
authors.lastname: Rezaee
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchini
authors.forename: Jin
authors.initials: J
authors.lastname: He
authors.forename: Marco
authors.initials: M
authors.lastname: Dal Molin
authors.forename: James F
authors.initials: JF
authors.lastname: Griffin
authors.forename: Helen
authors.initials: H
authors.lastname: Fedor
authors.forename: Shahriar
authors.initials: S
authors.lastname: Fesharakizadeh
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvia
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Claudio
authors.initials: C
authors.lastname: Bassi
authors.forename: John L
authors.initials: JL
authors.lastname: Cameron
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Lennon
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000473:pathology* / Q000601:surgery*; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology* / Q000601:surgery*; D002291:Carcinoma, Papillary / Q000473:pathology* / Q000601:surgery*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000473:pathology; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000601:surgery*; D017422:Sequence Analysis, DNA