title: p53, Ki-ras, and DNA ploidy in human pancreatic ductal adenocarcinomas.
abstract: Ki-ras mutations and DNA aneuploidy are common findings in human pancreatic ductal adenocarcinomas. An altered p53 tumor-suppressor gene has been suggested to cooperate with activated Ki-ras in malignant cellular transformation and could enhance genomic instability. We have investigated a panel of well-documented pancreatic carcinomas with defined ploidy and Ki-ras mutations for the presence and pattern of genetic alterations of the p53 gene, their coincidence with Ki-ras point mutations, and their correlation with DNA ploidy, tumor pathology, and clinical course. DNA was isolated from formalin-fixed and paraffin-embedded tumor tissue and polymerase-chain-reaction-amplified fragments of the p53 gene exons 5 to 9 were screened by the single-strand conformation polymorphism method. The positive cases were further examined for mutations by direct sequencing. Twenty-nine of seventy-one (41%) tumors showed mutations of the p53 gene, however, five tumors carried two mutations resulting in a total of 34/71 (48%) genetic alterations of the p53 gene. The majority were missense point mutations and distributed primarily within the evolutionary conserved domains (62%). Ten of Thirty-four (29%) affected the hotspot codons 248, 273, and 282, respectively, and 21/34 (62%) of the p53 gene mutations clustered on exons 7 and 8. Transitions (71%) predominated over transversions (15%), deletions were identified in 7/34 (21%) tumors. One third of the carcinomas showed both Ki-ras codon 12 and p53 gene mutations. p53 mutations correlated with distant metastasis (p < 0.05) and survival (p < 0.05). DNA triploidy was associated with a mutated Ki-ras gene (p < 0.05) as well as with double mutations of c-Ki-ras and p53 (p < 0.05). Unlike most other malignant tumors pancreatic ductal adenocarcinomas exhibit a significantly higher incidence of c-Ki-ras than p53 gene mutations. However, like other neoplasms p53 gene mutations seem to be associated with a metastatic phenotype possibly acquired during tumor progression.
authors.affiliation: Department of Internal Medicine, University of Innsbruck, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Weyrer
authors.forename: H
authors.initials: H
authors.lastname: Feichtinger
authors.forename: M
authors.initials: M
authors.lastname: Haun
authors.forename: G
authors.initials: G
authors.lastname: Weiss
authors.forename: D
authors.initials: D
authors.lastname: Ofner
authors.forename: A R
authors.initials: AR
authors.lastname: Weger
authors.forename: F
authors.initials: F
authors.lastname: Umlauft
authors.forename: K
authors.initials: K
authors.lastname: Grünewald
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011003:Ploidies
chemical_list: D004273:DNA, Neoplasm