Biologically-based mechanistic models of radiation-related carcinogenesis applied to epidemiological data

Abstract Purpose: Biologically-based mechanistic models that are used in combining current understanding of human carcinogenesis with epidemiological studies were reviewed. Assessment was made of how well they fit the data, whether they account for non-linear radiobiological low-dose effects, and whether they suggest any implications for the dose response at low doses and dose rates. However, the present paper does not make an attempt to provide a complete review of the existing literature on biologically-based models and their application to epidemiological data. Conclusion: In most studies the two-stage clonal expansion (TSCE) model of carcinogenesis was used. The model provided robust estimates of identifiable parameters and radiation risk. While relatively simple, it is flexible, so that more stages can easily be added, and tests made of various types of radiation action. In general, the model performed similarly or better than descriptive excess absolute and excess relative risk models, in terms of quality of fit and number of parameters. Only very rarely the shape of dose-response predicted by the models was investigated. For some tumors, when more detailed biological information was known, additional pathways were included in the model. The future development of these models will benefit from growing knowledge on carcinogenesis processes, and in particular from use of biobank tissue samples and advances in omics technologies. Their use appears a promising approach to investigate the radiation risk at low doses and low dose rates. However, the uncertainties involved are still considerable, and the models provide only a simplified description of the underlying complexity of carcinogenesis. Current assumptions in radiation protection including the linear-non-threshold (LNT) model are not in contradiction to what is presently known on the process of cancer development.

[1]  Malcolm Crick,et al.  United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) activities and issues , 2011 .

[2]  Mark P Little,et al.  Cancer models, genomic instability and somatic cellular Darwinian evolution , 2010, Biology Direct.

[3]  C. Nordling.  A New Theory on the Cancer-inducing Mechanism , 1953, British Journal of Cancer.

[4]  J. H. Hollomon,et al.  A hypothesis for the origin of cancer foci , 1951, Cancer.

[5]  W. Heidenreich,et al.  Studies of radon-exposed miner cohorts using a biologically based model: comparison of current Czech and French data with historic data from China and Colorado , 2004, Radiation and environmental biophysics.

[6]  W. Morgan,et al.  Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: II. Radiation-Induced Genomic Instability and Bystander Effects In Vivo, Clastogenic Factors and Transgenerational Effects , 2003, Radiation research.

[7]  J. Hendry,et al.  Lack of Correlation between Stem-Cell Proliferation and Radiation- or Smoking-Associated Cancer Risk , 2016, PloS one.

[8]  M. Kreuzer,et al.  Lung Cancer from Radon: A Two-Stage Model Analysis of the WISMUT Cohort, 1955–1998 , 2011, Radiation research.

[9]  A Reanalysis of Liver Cancer Incidence in Danish Patients Administered Thorotrast Using a Two-Mutation Carcinogenesis Model , 2002, Radiation research.

[10]  P. Armitage,et al.  The age distribution of cancer and a multi-stage theory of carcinogenesis , 1954, British Journal of Cancer.

[11]  Giovanni Parmigiani,et al.  Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation , 2013, Proceedings of the National Academy of Sciences.

[12]  E. Vasilenko,et al.  Lung cancer risk of Mayak workers: modelling of carcinogenesis and bystander effect , 2007, Radiation and environmental biophysics.

[13]  D. Brenner,et al.  A new view of radiation-induced cancer: integrating short- and long-term processes. Part I: Approach , 2009, Radiation and environmental biophysics.

[14]  D. Pierce,et al.  A model for radiation-related cancer suggested by atomic bomb survivor data. , 1999, Radiation research.

[15]  D. Brenner.  EXTRAPOLATING RADIATION-INDUCED CANCER RISKS FROM LOW DOSES TO VERY LOW DOSES , 2009, Health physics.

[16]  N. Hamada,et al.  Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects. , 2011, Current molecular pharmacology.

[17]  Dale L Preston,et al.  Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. , 2008, Journal of the National Cancer Institute.

[18]  E. Holmberg,et al.  Breast cancer risk and possible mechanisms of radiation-induced genomic instability in the Swedish hemangioma cohort after reanalyzed dosimetry. , 2015, Mutation research.

[19]  M. Little,et al.  A record-based case–control study of natural background radiation and the incidence of childhood leukaemia and other cancers in Great Britain during 1980–2006 , 2013, Leukemia.

[20]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Soile Tapio,et al.  Ionizing radiation biomarkers for potential use in epidemiological studies. , 2012, Mutation research.

[22]  M. Little.  Generalisations of the two-mutation and classical multi-stage models of carcinogenesis fitted to the Japanese atomic bomb survivor data , 1996 .

[23]  Philip Hahnfeldt,et al.  A new view of radiation-induced cancer: integrating short- and long-term processes. Part II: second cancer risk estimation , 2009, Radiation and environmental biophysics.

[24]  E. Holmberg,et al.  Breast cancer risk among Swedish hemangioma patients and possible consequences of radiation-induced genomic instability. , 2009, Mutation research.

[25]  Y. Hannun,et al.  Substantial contribution of extrinsic risk factors to cancer development , 2015, Nature.

[26]  Jan Christian Kaiser,et al.  Possible expressions of radiation-induced genomic instability, bystander effects or low-dose hypersensitivity in cancer epidemiology. , 2010, Mutation research.

[27]  W F Heidenreich,et al.  Exact solutions of the clonal expansion model and their application to the incidence of solid tumors of atomic bomb survivors , 1997, Radiation and environmental biophysics.

[28]  H. Zitzelsberger,et al.  Genomic copy number analysis of Chernobyl papillary thyroid carcinoma in the Ukrainian-American Cohort. , 2015, Carcinogenesis.

[29]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[30]  A. Morris,et al.  Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions , 2015, BDJ.

[31]  M. Little,et al.  A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data. , 2003, Mathematical biosciences.

[32]  G W Kneale,et al.  Risk of childhood cancer from fetal irradiation. , 1998, The British journal of radiology.

[33]  J. Samet,et al.  Radon-exposed underground miners and inverse dose-rate (protraction enhancement) effects. , 1995, Health physics.

[34]  B. Grosche,et al.  Lung cancer mortality in the European uranium miners cohorts analyzed with a biologically based model taking into account radon measurement error , 2012, Radiation and environmental biophysics.

[35]  E. Luebeck,et al.  Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects. , 1999, Radiation research.

[36]  E. Vasilenko,et al.  Lung cancer in Mayak workers: interaction of smoking and plutonium exposure , 2005, Radiation and environmental biophysics.

[37]  Nordling Co.  A New Theory on the Cancer-inducing Mechanism , 1953 .

[38]  M. Blettner,et al.  Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas , 2015, Carcinogenesis.

[39]  Martin A. Nowak,et al.  The role of chromosomal instability in tumor initiation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  Peter Jacob,et al.  Lung Cancer Mortality (1950–1999) among Eldorado Uranium Workers: A Comparison of Models of Carcinogenesis and Empirical Excess Risk Models , 2012, PloS one.

[41]  Mechanistic Models for Radiation Carcinogenesis and the Atomic Bomb Survivor Data , 2003, Radiation research.

[42]  Martin Vingron,et al.  Comprehensive genomic profiles of small cell lung cancer , 2015, Nature.

[43]  E. Luebeck,et al.  Multistage Models and the Incidence of Cancer in the Cohort of Atomic Bomb Survivors , 2002, Radiation research.

[44]  J. Kaiser,et al.  Genomic Instability and Radiation Risk in Molecular Pathways to Colon Cancer , 2014, PloS one.

[45]  M. Little,et al.  Risk coefficients for childhood cancer after intrauterine irradiation: a review , 2003, International journal of radiation biology.

[46]  E. Luebeck,et al.  Analysis of the incidence of solid cancer among atomic bomb survivors using a two-stage model of carcinogenesis. , 1997, Radiation research.

[47]  Antonio Gasparrini,et al.  Modeling exposure–lag–response associations with distributed lag non-linear models , 2013, Statistics in medicine.

[48]  E Georg Luebeck,et al.  Multistage carcinogenesis and the incidence of colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Adam P. Rosebrock,et al.  A global genetic interaction network maps a wiring diagram of cellular function , 2016, Science.

[50]  K. P. Kim,et al.  Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study , 2012, The Lancet.

[51]  W. Heidenreich,et al.  Use of the individual data of the a-bomb survivors for biologically based cancer models , 2010, Radiation and environmental biophysics.

[52]  W. Morgan.  Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: I. Radiation-Induced Genomic Instability and Bystander Effects In Vitro , 2003, Radiation research.

[53]  M. Brugmans,et al.  An analysis of bone and head sinus cancers in radium dial painters using a two-mutation carcinogenesis model. , 2000, Journal of radiological protection : official journal of the Society for Radiological Protection.

[54]  B. Grosche,et al.  Dose and dose-rate effects of ionizing radiation: a discussion in the light of radiological protection , 2015, Radiation and environmental biophysics.

[55]  Martin Röösli,et al.  Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study , 2015, Environmental health perspectives.

[56]  M. Eidemüller,et al.  Beyond Two-Stage Models for Lung Carcinogenesis in the Mayak Workers: Implications for Plutonium Risk , 2015, PloS one.

[57]  W. Heidenreich,et al.  Parameter Identifiability and Redundancy in a General Class of Stochastic Carcinogenesis Models , 2009, PloS one.

[58]  W. Heidenreich,et al.  A Biologically Based Model for Liver Cancer Risk in the Swedish Thorotrast Patients , 2003, Radiation research.

[59]  M. Eidemüller,et al.  Mechanistic study on lung cancer mortality after radon exposure in the Wismut cohort supports important role of clonal expansion in lung carcinogenesis , 2016, Radiation and environmental biophysics.

[60]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[61]  Steven J. M. Jones,et al.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma , 2014, Cell.

[62]  M. Egger,et al.  Response to “Comment on ‘Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study’” , 2015, Environmental health perspectives.

[63]  R. Platt.  CLONAL AGEING AND CANCER , 1955 .

[64]  B. Vogelstein,et al.  Variation in cancer risk among tissues can be explained by the number of stem cell divisions , 2015, Science.

[65]  P. Vineis,et al.  A stochastic carcinogenesis model incorporating multiple types of genomic instability fitted to colon cancer data. , 2008, Journal of theoretical biology.

[66]  A. Auvinen,et al.  Background radiation and childhood leukemia: A nationwide register‐based case‐control study , 2016, International journal of cancer.

[67]  M. Nowak,et al.  Only three driver gene mutations are required for the development of lung and colorectal cancers , 2014, Proceedings of the National Academy of Sciences.

[68]  D. Brenner,et al.  A new view of radiation-induced cancer. , 2011, Radiation protection dosimetry.

[69]  E. Luebeck,et al.  Impact of tumor progression on cancer incidence curves. , 2013, Cancer research.

[70]  J. Kaiser,et al.  Breast cancer risk in atomic bomb survivors from multi-model inference with incidence data 1958–1998 , 2011, Radiation and Environmental Biophysics.

[71]  W. Morgan.  Non-targeted and Delayed Effects of Exposure to Ionizing Radiation: I. Radiation-Induced Genomic Instability and Bystander Effects In Vitro , 2012 .

[72]  R Julian Preston,et al.  Integrating basic radiobiological science and epidemiological studies: why and how. , 2015, Health physics.

[73]  D. L. Preston,et al.  Solid Cancer Incidence in Atomic Bomb Survivors: 1958–1998 , 2007, Radiation research.

[74]  P. Armitage,et al.  A Two-stage Theory of Carcinogenesis in Relation to the Age Distribution of Human Cancer , 1957, British Journal of Cancer.

[75]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[76]  A. Feuchtinger,et al.  CLIP2 as radiation biomarker in papillary thyroid carcinoma , 2014, Oncogene.

[77]  D. Krewski,et al.  Biologically Based Analysis of Lung Cancer Incidence in a Large Canadian Occupational Cohort with Low-Dose Ionizing Radiation Exposure, and Comparison with Japanese Atomic Bomb Survivors , 2006, Journal of toxicology and environmental health. Part A.

[78]  J. Kaiser,et al.  Multi-model inference of adult and childhood leukaemia excess relative risks based on the Japanese A-bomb survivors mortality data (1950–2000) , 2011, Radiation and environmental biophysics.

[79]  N. Hamada.  What are the Intracellular Targets and Intratissue Target Cells for Radiation Effects? , 2014, Radiation research.

[80]  S. Moolgavkar,et al.  Two-event models for carcinogenesis: incidence curves for childhood and adult tumors☆ , 1979 .

[81]  M. Little,et al.  Stochastic modelling of colon cancer: is there a role for genomic instability? , 2006, Carcinogenesis.

[82]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[83]  C. Muirhead,et al.  Modelling lung tumour risk in radon-exposed uranium miners using generalizations of the two-mutation model of Moolgavkar, Venzon and Knudson , 2002, International journal of radiation biology.

[84]  M. Blettner,et al.  Integration of a radiation biomarker into modeling of thyroid carcinogenesis and post-Chernobyl risk assessment , 2016, Carcinogenesis.

[85]  M. Hochberg,et al.  Peto's paradox and human cancers , 2015, Philosophical Transactions of the Royal Society B: Biological Sciences.

[86]  W F Heidenreich,et al.  Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model , 2001, Radiation research.

[87]  J. Wienberg,et al.  Gain of chromosome band 7q11 in papillary thyroid carcinomas of young patients is associated with exposure to low-dose irradiation , 2011, Proceedings of the National Academy of Sciences.

[88]  Steven J. M. Jones,et al.  Comprehensive genomic characterization of squamous cell lung cancers , 2012, Nature.

[89]  M. Little.  Do non-targeted effects increase or decrease low dose risk in relation to the linear-non-threshold (LNT) model? , 2010, Mutation research.

[90]  L. Walsh,et al.  Modeling of cell inactivation and carcinogenesis in the atomic bomb survivors with applications to the mortality from all solid, stomach and liver cancer , 2008, Radiation and environmental biophysics.

[91]  P. Jacob,et al.  Comparison of mortality and incidence solid cancer risk after radiation exposure in the Techa River Cohort , 2010, Radiation and environmental biophysics.

[92]  岩崎 民子.  SOURCES AND EFFECTS OF IONIZING RADIATION : United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR 2000 Report to the General Assembly, with Scientific Annexes , 2002 .

[93]  W. Heidenreich,et al.  Promoting Action of Radiation in the Atomic Bomb Survivor Carcinogenesis Data? , 2007, Radiation research.

[94]  D. Brenner,et al.  Cancer risks after radiation exposure in middle age. , 2010, Journal of the National Cancer Institute.

[95]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[96]  Comparing regression methods for the two‐stage clonal expansion model of carcinogenesis , 2004, Statistics in medicine.