Abstract 3729: Heavy-ion space radiation exposure is a potential risk factor for gastrointestinal tumorigenesis even at extremely low doses

Abstract

Heavy-ion radiation (HZE)-induced carcinogenesis is a major concern in astronauts planning to undertake long-term deep space exploration, such as a mission to the Mars. Due to high-LET (linear energy transfer) characteristics of HZE ions present in deep space environment, the Mars mission is expected to substantially enhance gastrointestinal cancer risk in astronauts, relative to low-LET radiation. Previously, using three different mouse models of human colorectal cancer (APC min/+ , APC 1638N/+ and IL10 -/- mouse) we have unequivocally demonstrated a significantly higher risk of intestinal and colonic tumorigenesis after exposure to energetic heavy ions. This study aims to obtain quantitative GI-tumorigenesis data at space relevant doses (5-50 cGy) of heavy ions covering a broad-spectrum of linear energy transfer (2-148 keV/μm), relative to γ-radiation. The APC 1638N/+ mouse was used due to its best signal-to-noise ratio among all previously studied mouse models of human gastrointestinal cancer. Both female and male APC 1638N/+ mice (6-8 weeks, n=20) were whole-body exposed to sham-radiation, γ-rays, 4 He (2 keV/μm), 12 C (13 keV/μm), 16 O (22 keV/μm), 28 Si (69 keV/μm), and 56 Fe (148 keV/μm) -ion radiation at 5, 10, and 50 cGy dose at the NASA Space Radiation Laboratory (NSRL) in Brookhaven National Laboratory. Mice were euthanized at 150 d after radiation exposure and intestinal and colon tumor frequency and size were scored and analyzed as a function of dose, LET, and gender. The highest increase in tumor frequency was observed after 28 Si followed by 56 Fe, 16 O, 12 C, and 4 He radiation, and male preponderance for tumorigenesis was evident for each radiation type and dose. At 50 cGy dose, no significant difference in tumorigenesis was observed between γ and 4 He. However, at lower doses (5 and 10 cGy) significantly higher tumorigenesis was noted after 4 He exposure. Furthermore, calculation of relative biological effectiveness (RBE) for tumorigenesis showed the highest value with 28 Si and lower doses showed greater RBE relative to higher doses. No statistical difference in tumorigenesis pattern was evident between 16 O and 12 C at all studied doses. In addition no significant change in tumorigenesis pattern was evident between 28 Si and 56 Fe in female mice. Analysis showed greater tumorigenesis per unit of radiation (per cGy) at lower doses suggesting radiation-induced tumorigenesis reaching a saturation point at higher doses. The lack of understanding on radiation quality effects is one of the major uncertainties in space radiation exposure-associated cancer risk prediction. Using a broad-spectrum of HZE-ions we have demonstrated the dependence of gastrointestinal tumorigenesis on radiation quality even at very low doses, which has implications in cancer risk prediction for astronauts and also for accessing secondary cancer risks after particle radiotherapy. Citation Format: Shubhankar Suman, Santosh Kumar, Bo-Hyun Moon, Jerry Angdisen, Bhaskar VS Kallakury, Albert J. Fornace, Kamal Datta. Heavy-ion space radiation exposure is a potential risk factor for gastrointestinal tumorigenesis even at extremely low doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3729.