Abstract 2257: DNA adductome analysis in human colorectal tissues

Abstract

Abstract Due to recent advancement of DNA sequencing technologies, cancer genome analysis has shown that somatic mutations have different trends in various tissues and individuals. Some of trends has been associated with exposure of chemically reactive compounds derived from exogenous or endogenous sources and genetic deficiencies in DNA repair and DNA replication as mutational signatures. Accumulation of these information will ultimately expect to identify carcinogenic etiologies in an individual case. However, what types of DNA damage caused the mutational signatures and how extent they contribute to human carcinogenesis has not yet fully explained.To directly evaluate the chemical types of DNA damage in human colorectal tissues, we performed comprehensive identification of DNA adducts by a liquid chromatography coupled with mass spectrometry. In this DNA adductome methodology, genome DNA was enzymatically hydrolyzed into mononucleoside and separated using a reversed-phase chromatography. Chemical structure of DNA adducts including products of epigenetic modification in genome DNA was identified using column retention time and m/z of chemical standard library of DNA adducts. Peak areas of DNA adducts were normalized by that of naturally-occurring isotopologues of canonical DNA nucleoside and compared with clinicopathological information. We identified several DNA adducts in human colorectal tissue. These included DNA adducts of alkylation, oxidation, and lipid peroxidation. C5-methyl-2’-deoxycytidine was most abundant atypical DNA in human colorectal tissue and prevalent in all cases. C5-hydroxymethyl-2’-deoxycytdine was decreased in colorectal cancer cases compared with non-colorectal cancer cases. Other DNA adducts like 1,N6-etheno-2’-deoxyadenosine were present with group- or individual-specificity. Compared with our previous results of DNA adductome analysis in human stomach mucosae and kidney tissues, DNA adducts observed in human colorectal tissue showed some tissue specificity. We will discuss whether profiles of DNA adducts are based on similar contexts of chemical exposure among individuals. DNA adducts observed in our study potentially indicated chemical causes of DNA mutation in human colorectal tissue. We propose that the integration of DNA adductomics using mass spectrometric profiling with other genetic analysis such as mutational signature analysis leverage the exploration of chemical and genetic etiology in an individual carcinogenic context and evaluate gene-environment interaction in human carcinogenesis. Citation Format: Yuji Iwashita, Shunsuke Ohtsuka, Ippei Ohnishi, Yuto Matsushita, Takashi Yamashita, Keisuke Inaba, Atsuko Fukazawa, Hideto Ochiai, Keigo Matsumoto, Nobuhito Kurono, Yoshitaka Matsushima, Hiroki Mori, Shioto Suzuki, Shohachi Suzuki, Fumihiko Tanioka, Haruhiko Sugimura. DNA adductome analysis in human colorectal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2257.