title: Gene expression profiling of ampullary carcinomas classifies ampullary carcinomas into biliary-like and intestinal-like subtypes that are prognostic of outcome.
abstract: BACKGROUND
  Adenocarcinomas of the ampulla of Vater are classified as biliary cancers, though the exact epithelium of origin for these cancers is not known. We sought to molecularly classify ampullary adenocarcinomas in comparison to known adenocarcinomas of the pancreas, bile duct, and duodenum by gene expression analysis.
  
  
  METHODS
  We analyzed 32 fresh-frozen resected, untreated periampullary adenocarcinomas (8 pancreatic, 2 extrahepatic biliary, 8 duodenal, and 14 ampullary) using the Affymetrix U133 Plus 2.0 genome array. Unsupervised and supervised hierarchical clustering identified two subtypes of ampullary carcinomas that were molecularly and histologically characterized.
  
  
  RESULTS
  Hierarchical clustering of periampullary carcinomas segregated ampullary carcinomas into two subgroups, which were distinctly different from pancreatic carcinomas. Non-pancreatic periampullary adenocarcinomas were segregated into two subgroups with differing prognoses: 5 year RFS (77% vs. 0%, p = 0.007) and 5 year OS (100% vs. 35%, p = 0.005). Unsupervised clustering analysis of the 14 ampullary samples also identified two subgroups: a good prognosis intestinal-like subgroup and a poor prognosis biliary-like subgroup with 5 year OS of 70% vs. 28%, P = 0.09. Expression of CK7+/CK20- but not CDX-2 correlated with these two subgroups. Activation of the AKT and MAPK pathways were both increased in the poor prognostic biliary-like subgroup. In an independent 80 patient ampullary validation dataset only histological subtype (intestinal vs. pancreaticobiliary) was significantly associated with OS in both univariate (p = 0.006) and multivariate analysis (P = 0.04).
  
  
  CONCLUSIONS
  Gene expression analysis discriminated pancreatic adenocarcinomas from other periampullary carcinomas and identified two prognostically relevant subgroups of ampullary adenocarcinomas. Histological subtype was an independent prognostic factor in ampullary adenocarcinomas.
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. moverman@mdanderson.org
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Michael
authors.initials: M
authors.lastname: Davies
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Jiang
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhi-Qin
authors.forename: Katherine
authors.initials: K
authors.lastname: Stemke-Hale
authors.forename: Petra
authors.initials: P
authors.lastname: Rümmele
authors.forename: Christian
authors.initials: C
authors.lastname: Pilarsky
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.forename: Stanley
authors.initials: S
authors.lastname: Hamilton
authors.forename: Rosa
authors.initials: R
authors.lastname: Hwang
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Gauri
authors.initials: G
authors.lastname: Varadhachary
authors.forename: Bradley
authors.initials: B
authors.lastname: Broom
authors.forename: Huamin
authors.initials: H
authors.lastname: Wang
mesh_terms: D003138:Common Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism; D004379:Duodenal Neoplasms / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D040081:Protein Array Analysis