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Grant Details

Grant Number: 5R01CA047658-16 Interpret this number
Primary Investigator: Moolgavkar, Suresh
Organization: Fred Hutchinson Cancer Research Center
Project Title: Biomathematical Approaches to Cancer
Fiscal Year: 2005


Abstract

DESCRIPTION (provided by applicant): Clones of intermediate cells on the pathway to cancer, such as adenomatous polyps and altered hepatic foci, are often observed in humans and animals. These lesions provide insights into the earliest stages of the carcinogenic process. Because clonal expansion of cells that are partially transformed can increase the probability of cancer substantially, a quantitative understanding of these lesions is key to understanding cancer rates. The broad objective of this project is to continue the development of mathematical, statistical and computational tools, within the paradigm of multistage carcinogenesis, for the quantitative analyses of early lesions on the pathway to malignancy. The fundamental goals of these analyses are to study the temporal evolution of these lesions, to estimate the rate of initiation of the lesions, and the rates of cell division and apoptosis of the partially transformed cells that comprise the lesion. Information on such early lesions is typically available from initiation-promotion experiments, particularly in the rodent liver.In previous work mathematical expressions have been developed for the number and size distribution of intermediate lesions on the pathway to malignancy and used for analyses of initiation-promotion experiments in rat liver. This proposal plans to extend this work in light of new biological information. In addition to continuing work on analyses of liver foci in rodents, the research proposed here will investigate intermediate lesions in the human colon and in patients with Barrett's esophagus, a high-risk precursor condition for adenocarcinoma of the esophagus. In addition to the mathematical and statistical problems associated with clonal growth models within the paradigm of multistage carcinogenesis, both analyses of liver foci and analyses of lesions in Barrett's esophagus present diverse problems. Recognizing that modeling is an iterative process an integral part of this effort will be collaboration with experimentalists and human biologists, in particular Dr. Michael Schwarz, University of Tubingen, an expert on the rodent liver system, Dr. John Potter, an epidemiologist with expertise on colon cancer and Dr. Brian Reid, Director of the Seattle Barrett's Esophagus Project. The results of analyses will be used to help generate biologically relevant questions and hypotheses and to plan further experiments and studies, which, in turn, will lead to more refined models.



Publications

Evaluation of screening strategies for pre-malignant lesions using a biomathematical approach.
Authors: Jeon J. , Meza R. , Moolgavkar S.H. , Luebeck E.G. .
Source: Mathematical biosciences, 2008 May; 213(1), p. 56-70.
EPub date: 2008-02-26.
PMID: 18374369
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Analysis of lung cancer incidence in the Nurses' Health and the Health Professionals' Follow-Up Studies using a multistage carcinogenesis model.
Authors: Meza R. , Hazelton W.D. , Colditz G.A. , Moolgavkar S.H. .
Source: Cancer causes & control : CCC, 2008 Apr; 19(3), p. 317-28.
EPub date: 2007-12-06.
PMID: 18058248
Related Citations

Age effects and temporal trends in adenocarcinoma of the esophagus and gastric cardia (United States).
Authors: Jeon J. , Luebeck E.G. , Moolgavkar S.H. .
Source: Cancer causes & control : CCC, 2006 Sep; 17(7), p. 971-81.
PMID: 16841264
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A generalized Luria-Delbrück model.
Authors: Dewanji A. , Luebeck E.G. , Moolgavkar S.H. .
Source: Mathematical biosciences, 2005 Oct; 197(2), p. 140-52.
PMID: 16137718
Related Citations

Gestational mutations and carcinogenesis.
Authors: Meza R. , Luebeck E.G. , Moolgavkar S.H. .
Source: Mathematical biosciences, 2005 Oct; 197(2), p. 188-210.
PMID: 16087198
Related Citations

Modulation of liver tumorigenesis in Connexin32-deficient mouse.
Authors: Luebeck E.G. , Buchmann A. , Schneider D. , Moolgavkar S.H. , Schwarz M. .
Source: Mutation research, 2005-02-15; 570(1), p. 33-47.
PMID: 15680401
Related Citations

Commentary: Fifty years of the multistage model: remarks on a landmark paper.
Authors: Moolgavkar S.H. .
Source: International journal of epidemiology, 2004 Dec; 33(6), p. 1182-3.
EPub date: 2004-08-19.
PMID: 15319398
Related Citations

Multistage carcinogenesis and the incidence of human cancer.
Authors: Moolgavkar S.H. , Luebeck E.G. .
Source: Genes, chromosomes & cancer, 2003 Dec; 38(4), p. 302-6.
PMID: 14566848
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Exploring heterogeneity in tumour data using Markov chain Monte Carlo.
Authors: de Gunst M.C. , Dewanji A. , Luebeck E.G. .
Source: Statistics in medicine, 2003-05-30; 22(10), p. 1691-707.
PMID: 12720305
Related Citations

Multistage carcinogenesis and the incidence of colorectal cancer.
Authors: Luebeck E.G. , Moolgavkar S.H. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 2002-11-12; 99(23), p. 15095-100.
EPub date: 2002-11-01.
PMID: 12415112
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Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.
Authors: Luebeck E.G. , Heidenreich W.F. , Hazelton W.D. , Paretzke H.G. , Moolgavkar S.H. .
Source: Radiation research, 1999 Oct; 152(4), p. 339-51.
PMID: 10477911
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A method for parametric estimation of the number and size distribution of cell clusters from observations in a section plane.
Authors: de Gunst M.C. , Luebeck E.G. .
Source: Biometrics, 1998 Mar; 54(1), p. 100-12.
PMID: 9544509
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Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin.
Authors: Moolgavkar S.H. , Luebeck E.G. , Buchmann A. , Bock K.W. .
Source: Toxicology and applied pharmacology, 1996 May; 138(1), p. 31-42.
PMID: 8658510
Related Citations

Allelic instability in mitosis: a unified model for dominant disorders.
Authors: Zheng C.J. , Byers B. , Moolgavkar S.H. .
Source: Proceedings of the National Academy of Sciences of the United States of America, 1993-11-01; 90(21), p. 10178-82.
PMID: 8234274
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On the use of historical control data to estimate dose response trends in quantal bioassay.
Authors: Prentice R.L. , Smythe R.T. , Krewski D. , Mason M. .
Source: Biometrics, 1992 Jun; 48(2), p. 459-78.
PMID: 1637972
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Multistage carcinogenesis: population-based model for colon cancer.
Authors: Moolgavkar S.H. , Luebeck E.G. .
Source: Journal of the National Cancer Institute, 1992-04-15; 84(8), p. 610-8.
PMID: 1313509
Related Citations

Effects of polychlorinated biphenyls in rat liver: quantitative analysis of enzyme-altered foci.
Authors: Luebeck E.G. , Moolgavkar S.H. , Buchmann A. , Schwarz M. .
Source: Toxicology and applied pharmacology, 1991 Dec; 111(3), p. 469-84.
PMID: 1684071
Related Citations

Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions.
Authors: Dewanji A. , Moolgavkar S.H. , Luebeck E.G. .
Source: Mathematical biosciences, 1991 Apr; 104(1), p. 97-109.
PMID: 1804458
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Stochastic analysis of intermediate lesions in carcinogenesis experiments.
Authors: Luebeck E.G. , Moolgavkar S.H. .
Source: Risk analysis : an official publication of the Society for Risk Analysis, 1991 Mar; 11(1), p. 149-57.
PMID: 1828119
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The role of somatic mutations and cell replication kinetics in quantitative cancer risk assessment.
Authors: Moolgavkar S.H. , Luebeck E.G. .
Source: Progress in clinical and biological research, 1991; 369, p. 469-79.
PMID: 1835095
Related Citations

Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments--I. Single agent regimen.
Authors: Moolgavkar S.H. , Luebeck E.G. , de Gunst M. , Port R.E. , Schwarz M. .
Source: Carcinogenesis, 1990 Aug; 11(8), p. 1271-8.
PMID: 2143703
Related Citations

A two-mutation model for radon-induced lung tumors in rats.
Authors: Moolgavkar S.H. , Cross F.T. , Luebeck G. , Dagle G.E. .
Source: Radiation research, 1990 Jan; 121(1), p. 28-37.
PMID: 2153988
Related Citations

A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones.
Authors: Dewanji A. , Venzon D.J. , Moolgavkar S.H. .
Source: Risk analysis : an official publication of the Society for Risk Analysis, 1989 Jun; 9(2), p. 179-87.
PMID: 2762604
Related Citations

Cigarette smoking and lung cancer: reanalysis of the British doctors' data.
Authors: Moolgavkar S.H. , Dewanji A. , Luebeck G. .
Source: Journal of the National Cancer Institute, 1989-03-15; 81(6), p. 415-20.
PMID: 2783979
Related Citations

A stochastic two-stage model for cancer risk assessment. I. The hazard function and the probability of tumor.
Authors: Moolgavkar S.H. , Dewanji A. , Venzon D.J. .
Source: Risk analysis : an official publication of the Society for Risk Analysis, 1988 Sep; 8(3), p. 383-92.
PMID: 3201016
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