DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer.
To test the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis in susceptible individuals, aromatic DNA adducts and 8-hydroxyguanosine (8-OH-dG) were measured by (32)P-postlabeling and HPLC-EC, respectively, in 31 pancreatic tumors and 13 normal tissues adjacent to the tumor from patients with pancreatic cancer. Normal pancreatic tissues from 24 organ donors, from six patients with non-pancreatic cancers, and from five patients with chronic pancreatitis served as controls. It was found that tissue samples from patients with pancreatic cancer had significantly higher levels of both aromatic DNA adducts and 8-OH-dG compared with control samples. The mean (+/-S.D.) levels of aromatic DNA adducts were 101.8+/-74.6, 26.9+/-26.6, and 11.2+/-6.6 per 10(9) nucleotides in adjacent tissues, tumors, and controls, respectively. The mean (+/-S.D.) levels of 8-OH-dG were 11.9+/-9.6, 10.8+/-10.6, and 6.7+/-4.6 per 10(5) nucleotides in adjacent tissues, tumors, and controls, respectively. Polymorphisms of the CYP1A1, CYP2E1, NAT1, NAT2, GSTM1, MnSOD, and hOGG1 genes were determined in these patients. The level of aromatic DNA adducts was significantly associated with polymorphism of the CYP1A1 gene. No significant correlation was found between the level of 8-OH-dG and the MnSOD, GSTM1, and hOGG1 polymorphisms. However, one novel polymorphism/mutation of the hOGG1 gene was found in a pancreatic tumor. Mutation at codon 12 of the K-ras gene was found in 25 (81%) of 31 pancreatic tumors, including three G-to-A transitions and 22 G-to-T transversions. Patients with the G-to-T mutation had a significantly higher level of aromatic DNA adducts than those with G-to-A or wild-type codon (P=0.02). On the other hand, the K-ras mutation profile was not related to the level of 8-OH-dG. Given the limitation of sample size, these preliminary data lend further support the hypothesis that carcinogen exposure and oxidative stress are involved in pancreatic carcinogenesis.
Li
Donghui
D
Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, The University of Texas, 1400 Holcombe Blvd., Box 426, Houston, TX 77030, USA. dli@mdanderson.org
Firozi
Pervez F
PF
Zhang
Weiqing
W
Shen
Jianjun
J
DiGiovanni
John
J
Lau
Serrine
S
Evans
Douglas
D
Friess
Helmut
H
Hassan
Manal
M
Abbruzzese
James L
JL
D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D018736:DNA Adducts / Q000032:analysis*; D004249:DNA Damage; D005260:Female; D011905:Genes, ras; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic
D018736:DNA Adducts; D007527:Isoenzymes; D019363:Cytochrome P-450 CYP1A1; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1