Abstract 2199: CD14 gene polymorphisms associated with development of colorectal cancer subtypes among atomic bomb survivors in Japan

Abstract

Abstract Background: Epidemiological studies conducted among atomic bomb (A-bomb) survivors by the Radiation Effects Research Foundation (RERF) have indicated a significant radiation-dose-dependent increase in risks of certain cancers among survivors. The mechanisms for different organ susceptibilities to radiation have remained unclear. Epidemiological and biological data show that colorectal cancer (CRC) risk factors may vary by anatomic subsite. We categorized CRC into two subtypes: Proximal colon cancer (cecum, ascending colon, and transverse colon) and distal CRC (descending colon, sigmoid colon, rectosigmoid junction, and rectum). CD14 is known to enhance the inflammatory response in the colorectum by acting as a co-receptor to detect bacterial lipopolysaccharide and activating the production of inflammatory cytokine. In this study, we examined the association between polymorphisms of the cytokine CD14 gene and risks of CRC subtypes. Methods: We analyzed the follow-up data from the RERF Immunogenome Study Cohort of 4,673 A-bomb survivors at the baseline covering 1981-2005: a total of 222 CRC cases, comprising 81 proximal colon cancer cases and 131 distal CRC cases. We focused on the single nucleotide polymorphisms (SNPs) in the 5′-untranstated region of CD14 (CD14-C/A) and genotyped all cohort subjects. Relative risks (RRs) for CRC and subtypes were estimated. Results: RRs of all-subtypes-combined CRC or either of the subtypes significantly increased with increasing radiation dose. When dividing the subjects into 2 groups by genotypes (CD14-A/A homozygote and CD14-C/C homozygote combined with CD14-C/A heterozygote), A-bomb survivors with CD14-A/A homozygote revealed significantly higher RRs of all-subtype-combined CRC (1.52, 95%CI: 1.15-2.01) and distal CRC (1.76, 95% CI: 1.21-2.57) than those with CD14-C/C homozygote combined with CD14-C/A heterozygote. However, there was no significant difference between 2 genotype groups in proximal colon cancer (RR=1.24, 95% CI: 0.79-1.95). When categorizing radiation dose into 3 levels (< 5 mGy defined as “non-exposed”, 5-700 mGy, and >700 mGy), A-bomb survivors with CD14-A/A who were exposed to the highest radiation dose (>700 mGy) were at significantly higher risk of all-subtype-combined CRC (RR=2.53, 95%CI: 1.58-4.04) and distal CRC (RR=3.26, 95%CI: 1.71-6.23) than “non-exposed” survivors with CD14-C/C combined with CD14-C/A. Conclusion: These results suggest the potential involvement of a CD14-mediated inflammatory response in the development of radiation-associated CRC, specifically distal CRC, but not proximal colon cancer, among A-bomb survivors. This possibly contributes to the different susceptibilities of the proximal colon and distal colorectum to radiation exposure. Citation Format: Yiqun Hu, Kengo Yoshida, Junko Kajimura, Seishi Kyoizumi, Yoichiro Kusunoki, John Cologne, Waka Ohishi, Ikue Hayashi, Kei Nakachi, Tomonori Hayashi. CD14 gene polymorphisms associated with development of colorectal cancer subtypes among atomic bomb survivors in Japan. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2199. doi:10.1158/1538-7445.AM2014-2199