Grant Details
Grant Number: |
1R03CA084581-01 Interpret this number |
Primary Investigator: |
Li, Donghui |
Organization: |
University Of Texas Md Anderson Can Ctr |
Project Title: |
Genetic Susceptibility-Carcinogens in Pancreatic Cancer |
Fiscal Year: |
2000 |
Abstract
DESCRIPTION (Applicant's Description)
Pancreatic cancer contributes 5 percent of the total cancer death in this
country. It is a deadly disease with little known about the etiology. The
most consistently identified epidemiological risk factor for pancreatic cancer
is cigarette smoking. Dietary and industrial carcinogens have also been
suspected to be involved. Among all human cancers, pancreatic cancer has the
highest frequency (85 percent) of K-ras mutation and this event occurs in the
early stage of tumor development. Half of these mutations are C to A
transition, a point mutation induced by nitrosamines and other alkylating
agents in experimental animals. Nitrosamines are potent inducers of
pancreatic tumors in hamsters but not in rats. Variation in carcinogen
metabolizing enzymes between the two species has been credited for the
difference in their susceptibility to the exposure. Based on this
information, we propose two hypotheses: 1) Exposure to nitrosamines and other
alkylating agents leads to formation of DNA alkylation products which cause K-
ras mutations; 2) individuals with increased susceptibility to such exposure
are at greater risk for pancreatic cancer than are non-susceptible
individuals. To test these hypotheses, we will take a molecular
epidemiological approach with a case-control study. 100 newly diagnosed
pancreatic cancer patients will be matched with 100 non-cancer controls by
age, sex, ethnicity and smoking. We will measure carcinogen exposure by a
detailed questionnaire collecting information on occupation, smoking, alcohol
consumption and dietary history. We will determine genetic polymorphisms of
the carcinogen metabolizing enzymes, cytochrome P450 lAl and 2E1, N-acetyl
transferase 1 and 2, and glutathione S transferase. We will measure DNA
repair capacity by applying two carcinogen-induced DNA damage assays. We will
detect DNA damage derived from exposure to PAH and alkylating agents in the
target tissues of cases. The DNA damage profiles will be analyzed in relation
to K-ras mutation profiles in the tumors. Finally, the epidemiological data
will be analyzed along with the biomarker data to examine the gene and
environmental interactions. The long-term goal of our research is to identify
the genetic and environmental factors that influence the risk of developing
pancreatic cancer, therefore novel strategies can be developed for prevention
and early detection of the disease. This pilot study is intended to set the
stage for a large scale of investigation in the near future.
Publications
Haplotype of N-acetyltransferase 1 and 2 and risk of pancreatic cancer.
Authors: Jiao L.
, Doll M.A.
, Hein D.W.
, Bondy M.L.
, Hassan M.M.
, Hixson J.E.
, Abbruzzese J.L.
, Li D.
.
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2007 Nov; 16(11), p. 2379-86.
PMID: 18006927
Related Citations
Dietary mutagen exposure and risk of pancreatic cancer.
Authors: Li D.
, Day R.S.
, Bondy M.L.
, Sinha R.
, Nguyen N.T.
, Evans D.B.
, Abbruzzese J.L.
, Hassan M.M.
.
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2007 Apr; 16(4), p. 655-61.
PMID: 17416754
Related Citations
Polymorphisms of phase II xenobiotic-metabolizing and DNA repair genes and in vitro N-ethyl-N-nitrosourea-induced O6-ethylguanine levels in human lymphocytes.
Authors: Jiao L.
, Chang P.
, Firozi P.F.
, Lai D.
, Abbruzzese J.L.
, Li D.
.
Source: Mutation research, 2007-03-05; 627(2), p. 146-57.
EPub date: 2006-12-08.
PMID: 17158087
Related Citations
Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer.
Authors: Jiao L.
, Bondy M.L.
, Hassan M.M.
, Chang D.Z.
, Abbruzzese J.L.
, Evans D.B.
, Smolensky M.H.
, Li D.
.
Source: Cancer, 2007-03-01; 109(5), p. 840-8.
PMID: 17265526
Related Citations
The XPD Asp312Asn and Lys751Gln polymorphisms, corresponding haplotype, and pancreatic cancer risk.
Authors: Jiao L.
, Hassan M.M.
, Bondy M.L.
, Abbruzzese J.L.
, Evans D.B.
, Li D.
.
Source: Cancer letters, 2007-01-08; 245(1-2), p. 61-8.
EPub date: 2006-02-03.
PMID: 16458430
Related Citations
K-ras mutation and p16 and preproenkephalin promoter hypermethylation in plasma DNA of pancreatic cancer patients: in relation to cigarette smoking.
Authors: Jiao L.
, Zhu J.
, Hassan M.M.
, Evans D.B.
, Abbruzzese J.L.
, Li D.
.
Source: Pancreas, 2007 Jan; 34(1), p. 55-62.
PMID: 17198183
Related Citations
Single nucleotide polymorphisms of RecQ1, RAD54L, and ATM genes are associated with reduced survival of pancreatic cancer.
Authors: Li D.
, Frazier M.
, Evans D.B.
, Hess K.R.
, Crane C.H.
, Jiao L.
, Abbruzzese J.L.
.
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2006-04-10; 24(11), p. 1720-8.
EPub date: 2006-03-06.
PMID: 16520463
Related Citations
Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.
Authors: Li D.
, Liu H.
, Jiao L.
, Chang D.Z.
, Beinart G.
, Wolff R.A.
, Evans D.B.
, Hassan M.M.
, Abbruzzese J.L.
.
Source: Cancer research, 2006-03-15; 66(6), p. 3323-30.
PMID: 16540687
Related Citations
Selected polymorphisms of DNA repair genes and risk of pancreatic cancer.
Authors: Jiao L.
, Bondy M.L.
, Hassan M.M.
, Wolff R.A.
, Evans D.B.
, Abbruzzese J.L.
, Li D.
.
Source: Cancer detection and prevention, 2006; 30(3), p. 284-91.
EPub date: 2006-07-17.
PMID: 16844323
Related Citations
5,10-Methylenetetrahydrofolate reductase polymorphisms and the risk of pancreatic cancer.
Authors: Li D.
, Ahmed M.
, Li Y.
, Jiao L.
, Chou T.H.
, Wolff R.A.
, Lenzi R.
, Evans D.B.
, Bondy M.L.
, Pisters P.W.
, et al.
.
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005 Jun; 14(6), p. 1470-6.
PMID: 15941958
Related Citations
Molecular epidemiology of pancreatic cancer.
Authors: Li D.
, Jiao L.
.
Source: International journal of gastrointestinal cancer, 2003; 33(1), p. 3-14.
PMID: 12909734
Related Citations
DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer.
Authors: Li D.
, Firozi P.F.
, Zhang W.
, Shen J.
, DiGiovanni J.
, Lau S.
, Evans D.
, Friess H.
, Hassan M.
, Abbruzzese J.L.
.
Source: Mutation research, 2002-01-15; 513(1-2), p. 37-48.
PMID: 11719088
Related Citations
Molecular epidemiology of pancreatic cancer.
Authors: Li D.
.
Source: Cancer journal (Sudbury, Mass.), 2001 Jul-Aug; 7(4), p. 259-65.
PMID: 11561602
Related Citations