DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer

Donghui Li, Pervez F. Firozi, Weiqing Zhang, Jianjun Shen, John DiGiovanni, Serrine Lau, Douglas Evans, Helmut Friess, Manal Hassan, James L. Abbruzzese

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)37-48
Number of pages12
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume513
Issue number1-2
DOIs
StatePublished - Jan 15 2001
Externally publishedYes

Fingerprint

DNA Adducts
Genetic Polymorphisms
Pancreatic Neoplasms
Mutation
Neoplasms
Cytochrome P-450 CYP1A1
Codon
Carcinogenesis
Oxidative Stress
Nucleotides
Carcinogenicity Tests
Genes
Cytochrome P-450 CYP2E1
ras Genes
Chronic Pancreatitis
Carcinogens
Sample Size
High Pressure Liquid Chromatography
hydroxide ion
8-oxo-7-hydrodeoxyguanosine

Keywords

  • DNA adducts
  • Genetic polymorphisms
  • K-ras

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Genetics

Cite this

DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. / Li, Donghui; Firozi, Pervez F.; Zhang, Weiqing; Shen, Jianjun; DiGiovanni, John; Lau, Serrine; Evans, Douglas; Friess, Helmut; Hassan, Manal; Abbruzzese, James L.

In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis, Vol. 513, No. 1-2, 15.01.2001, p. 37-48.

Research output: Contribution to journalArticle

Li, D, Firozi, PF, Zhang, W, Shen, J, DiGiovanni, J, Lau, S, Evans, D, Friess, H, Hassan, M & Abbruzzese, JL 2001, 'DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer', Mutation Research - Genetic Toxicology and Environmental Mutagenesis, vol. 513, no. 1-2, pp. 37-48. https://doi.org/10.1016/S1383-5718(01)00291-1
Li, Donghui ; Firozi, Pervez F. ; Zhang, Weiqing ; Shen, Jianjun ; DiGiovanni, John ; Lau, Serrine ; Evans, Douglas ; Friess, Helmut ; Hassan, Manal ; Abbruzzese, James L. / DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. In: Mutation Research - Genetic Toxicology and Environmental Mutagenesis. 2001 ; Vol. 513, No. 1-2. pp. 37-48.
@article{c1fd7536f76b45978ade03bc1945c936,
title = "DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer",
abstract = "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.",
keywords = "DNA adducts, Genetic polymorphisms, K-ras",
author = "Donghui Li and Firozi, {Pervez F.} and Weiqing Zhang and Jianjun Shen and John DiGiovanni and Serrine Lau and Douglas Evans and Helmut Friess and Manal Hassan and Abbruzzese, {James L.}",
year = "2001",
month = "1",
day = "15",
doi = "10.1016/S1383-5718(01)00291-1",
language = "English (US)",
volume = "513",
pages = "37--48",
journal = "Mutation Research - Genetic Toxicology and Environmental Mutagenesis",
issn = "1383-5718",
publisher = "Elsevier",
number = "1-2",

}

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.

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

UR - http://www.scopus.com/inward/record.url?scp=0035863779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035863779&partnerID=8YFLogxK

U2 - 10.1016/S1383-5718(01)00291-1

DO - 10.1016/S1383-5718(01)00291-1

M3 - Article

VL - 513

SP - 37

EP - 48

JO - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

JF - Mutation Research - Genetic Toxicology and Environmental Mutagenesis

SN - 1383-5718

IS - 1-2

ER -