Grant Number:	5R01CA047658-12 Interpret this number
Primary Investigator:	Moolgavkar, Suresh
Organization:	Fred Hutchinson Cancer Research Center
Project Title:	Biomathematical Approaches to Cancer
Fiscal Year:	2000

DESCRIPTION (Adapted from applicant's abstract): The focus of this research will be on development of quantitative methods based on sound biological principles for the analyses of intermediate lesions on the carcinogenic pathway. Such lesions commonly arise in experimental carcinogenesis model systems, such as the mouse skin and rodent liver initiation-promotion systems. The ultimate goal of the analyses is the estimation of critical biological parameters such as the rate of initiation and the rates of cell division and death of initiated cells. Additionally, biologically-based quantitative analyses should lead to the generation of hypotheses to be tested in future experiments. The classical initiation-promotion experimental models, namely the mouse skin and the rodent liver systems, provide unique challenges to the analyst. In the rodent liver system, quantitative observations on three-dimensional objects, the altered hepatic foci, are made in two-dimensional sections under the microscope. Stereological methods must then be employed in order to reconstruct the three-dimensional picture. In the mouse skin system, premalignant lesions, the papillomas, and malignant lesions are directly visible without having to sacrifice the animal. Thus repeated observations are made on the same animal. This leads to the statistical problem of correlated longitudinal observations. The two-mutation clonal expansion model of carcinogenesis will form the basis of this work. This model, which postulates two rate-limiting steps on the pathway to malignancy and explicitly considers cell division and cell death, has natural interpretation within the initiation-promotion-progression paradigm of chemical carcinogenesis. The first rate-limiting event is identified with initiation, the clonal expansion of initiated cells with promotion, and the second rate-limiting event with progression. Four specific projects are planned. The first project has to do with incorporation of more realistic biological assumptions than have hitherto been used into the two-mutation clonal expansion model. In particular, more realistic mathematical descriptions of cell proliferation kinetics will be investigated. The second project will attempt to relax the strong stereological assumptions that have been made in the analyses of altered hepatic foci. Specifically, the assumption that these foci are perfect spheres will be relaxed. This will allow the application of the two-mutation model to experimental systems, such as the kidney and the pancreas, in which the assumption of spherical foci is untenable. The third project will develop quantitative methods for the analyses of very small altered hepatic foci, which are now being experimentally investigated with the development of the appropriate markers. The fourth project will develop methods for the application of the two-mutation clonal expansion model to the analyses of correlated longitudinal data on intermediate lesions, such as the papillomas arising in mouse skin painting experiments.




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.
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.
PMID: 18058248
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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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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
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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
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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 00:00:00.0; 570(1), p. 33-47.
PMID: 15680401
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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.
PMID: 15319398
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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 00:00:00.0; 22(10), p. 1691-707.
PMID: 12720305
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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 00:00:00.0; 99(23), p. 15095-100.
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
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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 00:00:00.0; 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 00:00:00.0; 84(8), p. 610-8.
PMID: 1313509
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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
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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
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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
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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
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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
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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 00:00:00.0; 81(6), p. 415-20.
PMID: 2783979
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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.
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