Abstract 3728: Inverse effect of 28Si and 56Fe radiation on intestinal tumorigenesis vs. carcinogenesis in APC1638N/+ mice

Abstract

Abstract Space radiation is a major risk factor for gastrointestinal (GI) cancer in astronauts and is a matter of concern. Earlier we have reported higher relative effects for intestinal tumorigenesis in APC1638N/+ mice after exposure to different heavy ion radiation spanning a range of LET values. The purpose of the current study was to histologically grade intestinal tumors into adenoma vs. adenocarcinoma and assess relative effects of different heavy ion radiation on tumorigenesis vs carcinogenesis. Tumors from male APC1638N/+ mice 150 d after exposure to whole-body sham, γ (0.3 keV/μm), 12C (13 keV/μm), 28Si (70 keV/μm), or 56Fe (148 keV/μm) radiation were harvested, fixed, paraffin embedded, and sectioned. Radiation doses were 0.1 Gy, 0.5 Gy and a equitoxic dose of 2.0 Gy γ-rays. H&E stained tumor sections from at least 50 tumors per study group were used for histological grading into adenoma and adenocarcinoma. Hotspot mutations for p53 and Kras genes were assessed using targeted PCR followed by amplicon sequencing in 20 tumors per study group. Our previous published data showed that among the three LETs tested relative intestinal tumorigenic effects (relative to γ-rays) peaked at a LET of 70 keV/μm (28Si) with 13 keV/μm (12C) showing the least effect and 148 keV/μm (56Fe) showing an intermediate effect. In contrast, the current study demonstrates that the frequency of adenocarcinoma peaked after 56Fe with the least effect after 12C and an intermediate effect after 28Si. Relative to γ-rays, the carcinoma frequencies were 42.4+0.9, 13.2+0.61 and 8.0+1.14 higher after 56Fe at doses of 0.1, 0.5 and 2.0 Gy respectively. Whereas the relative carcinoma frequencies of 34.2+1.35, 14.0+0.95 and 9.0+2.25 were observed after 28Si at doses of 0.1, 0.5 and 2.0 Gy respectively. While Kras mutation analysis of tumors did not show any difference among radiation types, p53 mutation analysis demonstrate a higher number of mutations in exon 5 in 56Fe relative to 28Si samples. Collectively, our data show that while LET-dependent tumorigenic effects followed a parabolic shape, carcinogenic effects followed a more linear-like pattern with highest adenocarcinoma percentage and frequency at 148 keV/μm (56Fe). Although inverse effects of LET on tumorigenesis vs. carcinogenesis could in part be attributed to the beams’ differential physical properties, our mutation data on p53 supports differential effects of the beams on tumor suppressor mutation. Citation Format: Santosh Kumar, Shubhankar Suman, Bhaskar V.s. Kallakury, Bo-Hyun Moon, Albert J. Fornace, Kamal Datta. Inverse effect of 28Si and 56Fe radiation on intestinal tumorigenesis vs. carcinogenesis in APC1638N/+ mice [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 3728.