TY - JOUR
T1 - DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer
AU - Li, Donghui
AU - Firozi, Pervez F.
AU - Zhang, Weiqing
AU - Shen, Jianjun
AU - DiGiovanni, John
AU - Lau, Serrine
AU - Evans, Douglas
AU - Friess, Helmut
AU - Hassan, Manal
AU - Abbruzzese, James L.
N1 - Funding Information:
This work was supported by NIH Grant CA84581, NIEHS Center Grant P30 ES07784, a PRS Grant from M.D. Anderson Cancer Center, The University of Texas, and the Tobacco Settlement Funds as appropriated by the Texas State Legislature.
PY - 2001/1/15
Y1 - 2001/1/15
N2 - 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 32P-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 109 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 105 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.
AB - 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 32P-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 109 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 105 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.
KW - DNA adducts
KW - Genetic polymorphisms
KW - K-ras
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U2 - 10.1016/S1383-5718(01)00291-1
DO - 10.1016/S1383-5718(01)00291-1
M3 - Article
C2 - 11719088
AN - SCOPUS:0035863779
SN - 1383-5718
VL - 513
SP - 37
EP - 48
JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis
IS - 1-2
ER -