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.
| Meza, Rafael; Hazelton, William D; Colditz, Graham A et al. (2008) Analysis of lung cancer incidence in the Nurses'Health and the Health Professionals'Follow-Up Studies using a multistage carcinogenesis model. Cancer Causes Control 19:317-28 |
| Jeon, Jihyoun; Meza, Rafael; Moolgavkar, Suresh H et al. (2008) Evaluation of screening strategies for pre-malignant lesions using a biomathematical approach. Math Biosci 213:56-70 |
| Jeon, Jihyoun; Luebeck, E Georg; Moolgavkar, Suresh H (2006) Age effects and temporal trends in adenocarcinoma of the esophagus and gastric cardia (United States). Cancer Causes Control 17:971-81 |
| Meza, Rafael; Luebeck, E Georg; Moolgavkar, Suresh H (2005) Gestational mutations and carcinogenesis. Math Biosci 197:188-210 |
| Luebeck, E Georg; Buchmann, Albrecht; Schneider, Daniela et al. (2005) Modulation of liver tumorigenesis in Connexin32-deficient mouse. Mutat Res 570:33-47 |
| Dewanji, A; Luebeck, E G; Moolgavkar, S H (2005) A generalized Luria-Delbruck model. Math Biosci 197:140-52 |
| Moolgavkar, Suresh H (2004) Commentary: Fifty years of the multistage model: remarks on a landmark paper. Int J Epidemiol 33:1182-3 |
| de Gunst, Mathisca C M; Dewanji, Anup; Luebeck, E Georg (2003) Exploring heterogeneity in tumour data using Markov chain Monte Carlo. Stat Med 22:1691-707 |
| Moolgavkar, Suresh H; Luebeck, E Georg (2003) Multistage carcinogenesis and the incidence of human cancer. Genes Chromosomes Cancer 38:302-6 |
| Luebeck, E Georg; Moolgavkar, Suresh H (2002) Multistage carcinogenesis and the incidence of colorectal cancer. Proc Natl Acad Sci U S A 99:15095-100 |
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