Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas.
Oncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events shape the resultant disease. We show here that concomitant expression of Kras(G12D) 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.
Izeradjene
Kamel
K
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Combs
Chelsea
C
Best
Melissa
M
Gopinathan
Aarthi
A
Wagner
Amary
A
Grady
William M
WM
Deng
Chu-Xia
CX
Hruban
Ralph H
RH
Adsay
N Volkan
NV
Tuveson
David A
DA
Hingorani
Sunil R
SR
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018291:Cystadenoma, Mucinous / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53