title: K-ras and p53 in pancreatic cancer: association with medical history, histopathology, and environmental exposures in a population-based study.
abstract: Pancreatic cancer is a highly fatal cancer with few identified risk factors. Increased risk of pancreatic cancer in tobacco smokers and among diabetic patients is well established, and some reports have suggested associations with coffee consumption and occupational exposure to organochlorines. At present, there is little information regarding the possible association of these risk factors with the known genetic alterations found in pancreatic cancers, such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor gene. Knowledge of such relationships may help to understand the molecular pathways of pancreatic tumorigenesis. We investigated the association between these molecular defects and risk factors for pancreatic cancer in 61 newly diagnosed patients identified through an ongoing study of pancreatic cancer in the San Francisco Bay Area. Interview information was obtained regarding environmental exposures, medical history, and demographic factors. Serum levels of dichlorodiphenyltrichloroethylene (DDE) and polychlorinated biphenyls were available on a subset of 24 patients. Tumor blocks were located from local hospitals and used for K-ras mutational analysis at codon 12 and for p53 protein immunohistochemistry. The molecular analyses were facilitated through the use of laser capture microdissection, which provides a reliable method to obtain almost pure populations of tumor cells. Mutations in K-ras codon 12 were found in 46 (75%) of 61 pancreatic cancers. A prior diagnosis of diabetes was significantly associated with K-ras negative tumors (P = 0.002, Fisher's exact test). The absence of this mutation was also associated with increased serum levels of DDE, although this association was not statistically significant (P = 0.16, Wilcoxon's test). There was no difference in polychlorinated biphenyl levels between the K-ras wild-type and mutant groups. Immunohistochemical staining for p53 protein did not differ by patient characteristics or clinical history, but significant associations were found with poor glandular differentiation (P = 0.002, chi2 trend test), severe nuclear atypia (P = 0.0007, chi2 trend test), and high tumor grade (P = 0.004, chi2 trend test). Our results are suggestive of the presence of K-ras codon 12 mutation-independent tumorigenesis pathways in patients with prior diabetes and possibly in patients with higher serum levels of DDE. Our results also support a role for the p53 tumor suppressor protein in the maintenance of genomic integrity.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Slebos
authors.forename: J A
authors.initials: JA
authors.lastname: Hoppin
authors.forename: P E
authors.initials: PE
authors.lastname: Tolbert
authors.forename: E A
authors.initials: EA
authors.lastname: Holly
authors.forename: J W
authors.initials: JW
authors.lastname: Brock
authors.forename: R H
authors.initials: RH
authors.lastname: Zhang
authors.forename: P M
authors.initials: PM
authors.lastname: Bracci
authors.forename: J
authors.initials: J
authors.lastname: Foley
authors.forename: P
authors.initials: P
authors.lastname: Stockton
authors.forename: L M
authors.initials: LM
authors.lastname: McGregor
authors.forename: G P
authors.initials: GP
authors.lastname: Flake
authors.forename: J A
authors.initials: JA
authors.lastname: Taylor
mesh_terms: D000368:Aged; D002273:Carcinogens / Q000009:adverse effects*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D048909:Diabetes Complications; D003633:Dichlorodiphenyl Dichloroethylene / Q000009:adverse effects; D004781:Environmental Exposure; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007306:Insecticides / Q000009:adverse effects; D008297:Male; D008487:Medical History Taking; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics*; D012307:Risk Factors
chemical_list: D002273:Carcinogens; D007306:Insecticides; D003633:Dichlorodiphenyl Dichloroethylene