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GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "incipient IPMNs".

Abstract
Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥ 1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N = 8) or ampullary adenocarcinoma (N = 3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N = 11) or intestinal (N = 5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.
AuthorsHanno Matthaei, Jian Wu, Marco Dal Molin, Chanjuan Shi, Sven Perner, Glen Kristiansen, Philipp Lingohr, Jörg C Kalff, Christopher L Wolfgang, Kenneth W Kinzler, Bert Vogelstein, Anirban Maitra, Ralph H Hruban
JournalThe American journal of surgical pathology (Am J Surg Pathol) Vol. 38 Issue 3 Pg. 360-3 (Mar 2014) ISSN: 1532-0979 [Electronic] United States
PMID24525507 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Biomarkers, Tumor
  • Chromogranins
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs
Topics
  • Adult
  • Aged
  • Biomarkers, Tumor (genetics)
  • Carcinoma, Pancreatic Ductal (classification, genetics, pathology, surgery)
  • Carcinoma, Papillary (classification, genetics, pathology, surgery)
  • Chromogranins
  • DNA Mutational Analysis
  • Diagnosis, Differential
  • Female
  • GTP-Binding Protein alpha Subunits, Gs (genetics)
  • Genetic Predisposition to Disease
  • Genetic Testing (methods)
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Grading
  • Neoplasms, Cystic, Mucinous, and Serous (classification, genetics, pathology, surgery)
  • Pancreatic Cyst (classification, genetics, pathology, surgery)
  • Pancreatic Neoplasms (classification, genetics, pathology, surgery)
  • Phenotype
  • Predictive Value of Tests
  • Switzerland
  • Tumor Burden
  • United States

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