## 1 Introduction
### Oncologic Effects  
Even during short-duration spaceflight, the stochastic nature of cancer development makes it possible that space radiation exposure could cause cancer via epigenomic modifications [63]. Currently, our epidemiological understanding of radiation-induced cancer risk is based primarily on atomic bomb survivors and accidental radiation exposures, which both show a clear association between radiation exposure and cancer risk [169; 170]. However, these studies are hard to generalize to spaceflight as the patient populations vary significantly (generally healthy astronauts vs. atomic bomb survivors [NCRP 126]) [171]. Moreover, the radiation encountered in space is notably different than that associated with atomic bomb exposure. Most terrestrial exposures are based on low LET radiation (e.g., atomic bomb survivors received \(<\)1% dose from high LET neutrons) [172], whereas space radiation is comprised of higher LET ions (solar energetic particles and galactic cosmic rays) [173; 174].  
During long-duration spaceflight, our current understanding of cancer risk is also largely unknown. Our current epidemiologic understanding of long-duration radiation exposure and cancer risk is primarily based on the study of chronic occupational exposures and medically exposed individuals, supplemented with data obtained from animal studies, which are again based overwhelmingly on low LET radiation [169; 175; 176; 177]. In animal studies, exposure to ionizing radiation (up to 13.5 months) has been associated with an increased risk of developing a variety of cancers [162; 178; 179; 180]. Ionizing radiation exposure may cause DNA methylation patterns similar to the specific patterns observed in human adenocarcinomas and squamous cell carcinomas [63]; however, this response is not yet certain [181; 182].  
For the purposes of risk prediction, the elevated biological potency of heavy ions is modeled through concepts such as the radiation weighting factor, with NASA recently releasing unique quality factors (\(Q_{NASA}\)) focused on high density tracks [183]. Although these predictive models can only estimate the impact of radiation exposure, extrapolation of current terrestrial-based data suggest that this risk could be at least substantial for astronauts. NASA, for example, has updated crew permissible career exposure limits to 0.6 Sv, independent of age and sex. This degree of exposure results in a 2-3% mean increased risk of death from radiation carcinogenesis (NCRP 2021) [184]. This limit would be reached between 200 and 400 days of space travel (depending on degree of radiation shielding) [48].  
Further research is urgently needed to understand the true risk of space radiation exposure. This is especially important for individuals with certain genotype-phenotype profiles (e.g., \(BRCA1\) or DNA methylation signatures) who may be more sensitive to the effects of radiation exposure. Most importantly, the utilization of genotype-phenotype profiles of astronauts or space travelers is valuable not just for pre-flight screening, but also during in-flight travel, especially for long-duration flights to deeper space. An individual's genetic makeup will in-variably change during spaceflight due to the shifting epigenetic microenvironment. Future crewed-missions to deep space will have to adapt to these anticipated changes, be-come aware of impending red-flag situations, and determine whether any meaningful shift or change to ones' genetic makeup is possible. For example, personalized radiation shields could potentially be tailored to an individuals' genotype phenotype profile, individualized pulmonary capillary wedge pressure under microgravity may be different due to transient changes in left atrial structure, or preflight analysis of the globin gene for the prediction of space anemia [50; 129; 185]. This research should be designed to identify the radiation type, dose, quality, frequency, and duration of exposure required for cancer development.