title: Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers.
abstract: Recent studies on small series of pancreatic cancer (PC) with foci of pancreatic intraepithelial neoplasia (PanIN), a putative precursor lesion, have shown that multiple K-RAS mutations may coexist in the same neoplastic pancreas. To see whether mutant-K-RAS polyclonality is a common and specific feature of pancreatic carcinogenesis, we investigated a unselected series of periampullary cancers (41 pancreatic, 13 biliary and two ampullary adenocarcinomas). After hemi-nested polymerase chain reaction (PCR), mutations identified with single strand conformation polymorphism (SSCP) were confirmed by allele-specific PCR and sequencing. K-RAS codon 12 was mutated in 34 (83%) pancreatic cancers and in 11 (85%) biliary cancers. Multiple distinct K-RAS mutations were found in 16 PC (39% of all cases, 47% of those with mutated K-RAS) and in eight biliary cancers (62 and 72%, respectively). In PC, multiple K-RAS mutations were more frequent (P<0.001) in cancers with (nine of 12, 75%) than in those without detectable PanIN (seven of 29, 24%). Individual precursor lesions of the same neoplastic pancreas were found to harbor distinct mutations. Results show that multiple K-RAS mutations are frequent both in PC with associated PanIN and in biliary cancers, and indicate that clonally distinct precursor lesions of PC might variably contribute to tumor development.
authors.affiliation: Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan, 20089 Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.forename: Ombretta
authors.initials: O
authors.lastname: Orbetegli
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbi
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000483:Alleles; D014670:Ampulla of Vater; D001650:Bile Duct Neoplasms / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics; D003062:Codon / Q000235:genetics; D003138:Common Bile Duct Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D006965:Hyperplasia; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011230:Precancerous Conditions / Q000235:genetics*
chemical_list: D003062:Codon; D004273:DNA, Neoplasm