Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers.
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.
Laghi
Luigi
L
Division of Gastroenterology, Istituto Clinico Humanitas, Rozzano, Milan, 20089 Italy.
Orbetegli
Ombretta
O
Bianchi
Paolo
P
Zerbi
Alessandro
A
Di Carlo
Valerio
V
Boland
C Richard
CR
Malesci
Alberto
A
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*
D003062:Codon; D004273:DNA, Neoplasm