title: 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.
authors: Departments of *Pathology ††Oncology #Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine ‡Ludwig Center for Cancer Genetics **Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD §Department of Pathology, Microbiology, Immunology, Vanderbilt University Medical Center, Nashville, TN Departments of †General, Visceral, Thoracic and Vascular Surgery ¶Prostate Cancer Research ∥Institute of Pathology, University of Bonn, Bonn, Germany.
authors: Hanno
authors: H
authors: Matthaei
authors: Jian
authors: J
authors: Wu
authors: Marco
authors: M
authors: Dal Molin
authors: Chanjuan
authors: C
authors: Shi
authors: Sven
authors: S
authors: Perner
authors: Glen
authors: G
authors: Kristiansen
authors: Philipp
authors: P
authors: Lingohr
authors: Jörg C
authors: JC
authors: Kalff
authors: Christopher L
authors: CL
authors: Wolfgang
authors: Kenneth W
authors: KW
authors: Kinzler
authors: Bert
authors: B
authors: Vogelstein
authors: Anirban
authors: A
authors: Maitra
authors: Ralph H
authors: RH
authors: Hruban
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002291:Carcinoma, Papillary / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002864:Chromogranins; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010181:Pancreatic Cyst / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010190:Pancreatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010641:Phenotype; D011237:Predictive Value of Tests; D013557:Switzerland; D047368:Tumor Burden; D014481:United States
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs