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

Hanno Matthaei, Jian Wu, Marco Dal Molin, Chanjuan Shi, Sven Perner, Glen Kristiansen, Philipp Lingohr, Jörg C. Kalff, Christopher Wolfgang, Kenneth W Kinzler, Bert Vogelstein, Anirban Maitra, Ralph H Hruban

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)360-363
Number of pages4
JournalAmerican Journal of Surgical Pathology
Volume38
Issue number3
DOIs
StatePublished - Mar 2014

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Pancreatic Cyst
Mutation
Neoplasms
Codon
Adenocarcinoma

Keywords

  • GNAS mutation
  • incipient IPMN
  • intraductal papillary mucinous neoplasm
  • pancreatic cyst

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine
  • Surgery

Cite this

GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "Incipient IPMNs". / Matthaei, Hanno; Wu, Jian; Dal Molin, Marco; Shi, Chanjuan; Perner, Sven; Kristiansen, Glen; Lingohr, Philipp; Kalff, Jörg C.; Wolfgang, Christopher; Kinzler, Kenneth W; Vogelstein, Bert; Maitra, Anirban; Hruban, Ralph H.

In: American Journal of Surgical Pathology, Vol. 38, No. 3, 03.2014, p. 360-363.

Research output: Contribution to journalArticle

Matthaei, Hanno ; Wu, Jian ; Dal Molin, Marco ; Shi, Chanjuan ; Perner, Sven ; Kristiansen, Glen ; Lingohr, Philipp ; Kalff, Jörg C. ; Wolfgang, Christopher ; Kinzler, Kenneth W ; Vogelstein, Bert ; Maitra, Anirban ; Hruban, Ralph H. / GNAS sequencing identifies IPMN-specific mutations in a subgroup of diminutive pancreatic cysts referred to as "Incipient IPMNs". In: American Journal of Surgical Pathology. 2014 ; Vol. 38, No. 3. pp. 360-363.
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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.",
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