KrasG12D and Smad4/Dpc4 Haploinsufficiency Cooperate to Induce Mucinous Cystic Neoplasms and Invasive Adenocarcinoma of the Pancreas

Kamel Izeradjene, Chelsea Combs, Melissa Best, Aarthi Gopinathan, Amary Wagner, William M. Grady, Chu Xia Deng, Ralph H. Hruban, N. Volkan Adsay, David A. Tuveson, Sunil R. Hingorani

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events shape the resultant disease. We show here that concomitant expression of KrasG12D and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas. Disease evolves along a progression scheme analogous to, but distinct from, the classical PanIN-to-ductal adenocarcinoma sequence, and also portends a markedly different prognosis. Progression of MCNs is accompanied by LOH of Dpc4 and mutation of either p53 or p16. Thus, these distinct phenotypic routes to invasive adenocarcinoma nevertheless share the same overall mutational spectra. Our findings suggest that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology.

Original languageEnglish (US)
Pages (from-to)229-243
Number of pages15
JournalCancer cell
Volume11
Issue number3
DOIs
StatePublished - Mar 13 2007

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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