title: Evaluating biomarkers to model cancer risk post cosmic ray exposure.
abstract: Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure, the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing biomarkers and to evaluate the potential for biomarkers to inform models of post exposure cancer risk. Because cellular stress response pathways to space radiation and environmental carcinogens share common nodes, biomarker-driven risk models may be broadly applicable for estimating risks for other carcinogens.
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Deepa M
authors.initials: DM
authors.lastname: Sridharan
authors.affiliation: UT Southwestern Medical Center, Dallas, TX, United States.
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
authors.affiliation: Langley Research Center, Langley Research Center (LaRC), VA, United States.
authors.forename: Steve R
authors.initials: SR
authors.lastname: Blattnig
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Sylvain V
authors.initials: SV
authors.lastname: Costes
authors.affiliation: Emory University, Atlanta, GA, United States.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
authors.affiliation: Emory University, Atlanta, GA, United States.
authors.forename: William S
authors.initials: WS
authors.lastname: Dynan
authors.affiliation: CCSB-Tufts School of Medicine, Boston, MA, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Hahnfeldt
authors.affiliation: CCSB-Tufts School of Medicine, Boston, MA, United States.
authors.forename: Lynn
authors.initials: L
authors.lastname: Hlatky
authors.affiliation: Wyle Science, Technology & Engineering Group, Houston, TX, United States.
authors.forename: Yared
authors.initials: Y
authors.lastname: Kidane
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Kronenberg
authors.affiliation: CCSB-Tufts School of Medicine, Boston, MA, United States.
authors.forename: Mamta D
authors.initials: MD
authors.lastname: Naidu
authors.affiliation: Houston Methodist Research Institute, Houston, TX, United States.
authors.forename: Leif E
authors.initials: LE
authors.lastname: Peterson
authors.affiliation: Wyle Science, Technology & Engineering Group, Houston, TX, United States.
authors.forename: Ianik
authors.initials: I
authors.lastname: Plante
authors.affiliation: Wyle Science, Technology & Engineering Group, Houston, TX, United States.
authors.forename: Artem L
authors.initials: AL
authors.lastname: Ponomarev
authors.affiliation: UT Southwestern Medical Center, Dallas, TX, United States.
authors.forename: Janapriya
authors.initials: J
authors.lastname: Saha
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA, United States.
authors.forename: Antoine M
authors.initials: AM
authors.lastname: Snijders
authors.affiliation: UT Southwestern Medical Center, Dallas, TX, United States.
authors.forename: Kalayarasan
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Exogen Biotechnology, Inc., Berkeley, CA, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Emory University, Atlanta, GA, United States.
authors.forename: Erica
authors.initials: E
authors.lastname: Werner
authors.affiliation: Lawrence Berkeley National Laboratory, Berkeley, CA, United States. Electronic address: jmpluth@lbl.gov.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pluth
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D003359:Cosmic Radiation / Q000009:adverse effects*; D004307:Dose-Response Relationship, Radiation; D005069:Evaluation Studies as Topic; D006801:Humans; D009381:Neoplasms, Radiation-Induced / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D018570:Risk Assessment
chemical_list: D015415:Biomarkers
keywords: Biomarkers; Cancer risk; HZE; Modeling; Space radiation