title: Molecular Evidence for Monoclonal Skip Progression in Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas.
abstract: To clarify clonality of distinct multisegmental main duct (MD)-intraductal papillary mucinous neoplasms (IPMNs) using microarray analysis.
  
  
  
  IPMNs represent a pancreatic ductal cell field defect, which causes multiple occurrences of lesions. In addtion, it has been speculated that MD-IPMNs display features of monoclonal skip progression.
  
  
  
  Total RNA was extracted from fresh-frozen tissue samples of metachronous MD-IPMNs and nonneoplastic pancreas tissue from the same pancreas from two individuals, and whole human genome microarray analysis was performed. Formalin-fixed paraffin-embedded tissue specimens from 28 distinct IPMNs were then collected from 12 patients, genomic DNA was extracted, and GNAS/KRAS mutational status was investigated. Immunohistochemical analysis was performed to validate the expression pattern of the indicated proteins.
  
  
  
  Microarray analysis revealed that metachronous MD-IPMNs from the same individual displayed pair-wise correlation coefficients of 0.9523 and 0.9512. In contrast, MD-IPMNs of the same histological grade from different individuals displayed coefficients of 0.8092 and 0.8211. Scatter plot analysis revealed that metachronous MD-IPMNs from the same individual displayed a closer linear relationship. Furthermore, heat map and hierarchical cluster analyses revealed that metachronous MD-IPMNs from the same individual were classified in the same branch, and the gene expression patterns were similar. The GNAS/KRAS mutational statuses of distinct MD-IPMNs were consistent with each other. Immunohistochemical assessment of five specific proteins demonstrated that the same expression pattern between two lesions was observed in 95% of the samples.
  
  
  
  These findings using molecular analyses indicate that MD-IPMNs might display features of monoclonal skip progression.
authors.affiliation: *Departments of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan†Departments of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Date
authors.forename: Takao
authors.initials: T
authors.lastname: Ohtsuka
authors.forename: Takaaki
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Koji
authors.initials: K
authors.lastname: Tamura
authors.forename: Hideyo
authors.initials: H
authors.lastname: Kimura
authors.forename: Taketo
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochidome
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Mori
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002864:Chromogranins / Q000235:genetics; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010180:Pancreatectomy / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012494:Sampling Studies; D012680:Sensitivity and Specificity
chemical_list: D002864:Chromogranins; C117307:KRAS protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D016283:Proto-Oncogene Proteins p21(ras)