Evaluating the Number of Stages in Development of Squamous Cell and Adenocarcinomas across Cancer Sites Using Human Population-Based Cancer Modeling

BACKGROUND: Adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) differ by clinical and molecular characteristics. We evaluated the characteristics of carcinogenesis by modeling the age patterns of incidence rates of ACs and SCCs of various organs to test whether these characteristics differed between cancer subtypes. METHODOLOGY/PRINCIPAL FINDINGS: Histotype-specific incidence rates of 14 ACs and 12 SCCs from the SEER Registry (1973-2003) were analyzed by fitting several biologically motivated models to observed age patterns. A frailty model with the Weibull baseline was applied to each age pattern to provide the best fit for the majority of cancers. For each cancer, model parameters describing the underlying mechanisms of carcinogenesis including the number of stages occurring during an individual's life and leading to cancer (m-stages) were estimated. For sensitivity analysis, the age-period-cohort model was incorporated into the carcinogenesis model to test the stability of the estimates. For the majority of studied cancers, the numbers of m-stages were similar within each group (i.e., AC and SCC). When cancers of the same organs were compared (i.e., lung, esophagus, and cervix uteri), the number of m-stages were more strongly associated with the AC/SCC subtype than with the organ: 9.79±0.09, 9.93±0.19 and 8.80±0.10 for lung, esophagus, and cervical ACs, compared to 11.41±0.10, 12.86±0.34 and 12.01±0.51 for SCCs of the respective organs (p<0.05 between subtypes). Most SCCs had more than ten m-stages while ACs had fewer than ten m-stages. The sensitivity analyses of the model parameters demonstrated the stability of the obtained estimates. CONCLUSIONS/SIGNIFICANCE: A model containing parameters capable of representing the number of stages of cancer development occurring during individual's life was applied to the large population data on incidence of ACs and SCCs. The model revealed that the number of m-stages differed by cancer subtype being more strongly associated with ACs/SCCs histotype than with organ/site

The Role of Apoptosis in the Development of Radiation-Induced Genome Instability under Chronic Radiation Expos

Apoptosis resulting from a high frequency of damage to the cells genetic material and manifested at late time after exposure is regarded as an evidence of radiation-induced genomic instability. On the other hand, apoptosis disruption may lie behind preservation of cells with genetic anomalies, and become thereby one of the mechanisms of genomic instability. Techa riverside residents, have been chronically exposed to radiation since 1949 as a result of the Mayak PA activities. Maximum dose rates were 0.4-0.5 Gy/year during the early years. Two groups (168 exposed individuals and 118 unexposed controls) were studied with the aim to assess the intensity of peripheral blood lymphocyte apoptosis 55-58 years after the onset of radiation exposure. Apoptosis was assessed based on morphological criteria, using the TUNEL assay, by typing CD95 positive lymphocytes. To assess the apoptotic reserve of the peripheral blood lymphocytes, in-vitro additional irradiation at a dose of 1 Gy, and 24-hour incubation was used. Increase of apoptosis in exposed individual was revealed based on morphological criteria () (12.3±0.6 in exposed vs 9.1±0.8 control subjects) and the findings of the TUNEL assay () (2.4±0,3 in exposed vs 0.9±0.2 control subjects). No dependence of CD95 positive lymphocytes on radiation factor was registered (8.0±0.4 in exposed vs 7.4±0.6 control subjects). A modeling approach was used to estimate the fraction of cells with broken apoptosis from these two groups. In this approach dynamics of cell states after in vitro irradiation is modeled by the 4-compartment model with compartments of i) cell with deficient apoptosis, ii) normal cells, iii) damaged cells, and iv) cells identified as apoptotic. The estimation of model parameters resulted in identifying the fraction of cells with broken apoptosis from the initial blood sample. It can be concluded based on the study results that: (1) chronically exposed individuals manifest an increased rate of peripheral blood lymphocyte apoptosis decades after dose rates returned to the background level, (2) using the method of genotoxic exposure (standard in-vitro irradiation), it was possible to detect a higher frequency of apoptotic abnormalities in chronically exposed individuals vs that in the controls. Thus, the study has provided a convincing evidence of the important role played by apoptosis in the development of radiation-induced genomic instability in man

A New Model of Short- and Long-term Effects of Exposure to Ionizing Radiation in Hematopoietic System of Human

In this report we present a new model of the hematopoietic system for humans exposed to chronic and acute ionizing radiation (IR). This model is capable of describing both short-term deterministic effects represented by the process of the loss and replacement of cells and long-term stochastic effects such as carcinogenesis. The model combines and further extends the ideas used in: i) models of hematopoietic system as formulated and developed by Mackey and colleagues, and ii) the carcinogenesis model of breaking barrier mechanisms recently developed by our group. The generalized model of hematopoiesis relates the hematopoietic stem cell compartment with all lines of peripheral blood (red blood cells, white cells and platelets). Exposure to IR is described within the one-hit-one target theory, though the generalizations to include more sophisticated approaches as well as bystander effect are discussed. The concept of breaking barrier mechanisms is used to describe carcinogenesis represented as a dynamic trade-off between two antagonistic forces or processes, promoting or hindering carcinogenesis at its different stages (initiation, promotion, conversion). The model was formulated in such a way that it represents the three levels of the organisms vital organization: i) a cellular level, where the dynamics of the processes of cell kinetics, reparation, and apoptosis, are defined, ii) a level of human organism, where covariates describing health states are measured, and iii) a population, where such characteristics as incidence and mortality rates associated with cancer are predicted. One advantage of the suggested modeling approach is in the possibility of the natural combining of different measurements including age-specific hazard rate and measures, characterizing fractions of cells with breaking barriers. Another advantage is in the broad spectrum of areas of potential applications, including: i) further investigation of mechanisms of health effects induced by IR, i.e., carcinogenesis or reactions of radiosensitive tissues, ii) development of strategies of radiation protection through calculating risks for specific population groups, iii) investigation of normal tissue reaction during radiological treatment in radiation oncology, iv) biodosimetry, v) radiobiology, e.g., investigating IR induced genomic instability, and vi) development of methods of individual prognostication. The model can be estimated using information on characteristics of hematopoiesis and cell damage by IR available in literature. Using the estimated model we performed simulation studies allowing for identification of dose characteristics of acute or chronic exposure for which disorders in hematopoietic systems occur in a certain fraction of the exposed population