Geospatial Assessments of DNA Adducts in the Human Stomach: A Model of Field Cancerization

Abstract

Background: Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. Methods: Seven DNA adducts, C5-methyl-2′-deoxycytidine, 2′-deoxyinosine, C5-hydroxymethyl-2′-deoxycytidine, N6-methyl-2′-deoxyadenosine, 1,N6-etheno-2′-deoxyadenosine, N6-hydroxymethyl-2′-deoxyadenosine, and C8-oxo-2′-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of the stomach, and the mucosae distant from and near the tumor were compared to determine whether the location preference of cancer in the stomach could be explained by the distribution of these DNA adducts. Comparisons were conducted considering the tumor locations and operation methods. Conclusions: Regarding the DNA adducts investigated, significant differences in quantities and locations in the whole stomach were not noted; thus, these DNA adducts do not explain the preferential occurrence of cancer in particular locations of the human stomach.

Non-CpG sites preference in G:C > A:T transition of TP53 in gastric cancer of Eastern Europe (Poland, Romania and Hungary) compared to East Asian countries (China and Japan)

“…These adducts may the first step in human gastric carcinogenesis [39]; however, determining whether the G:C > A:T mutations at non-CpG sites of GC in Eastern Europe involve diet-related N-nitroso compounds remains a challenge. The generation of DNA adducts has been attributed to alkylating agents hypothetically [40][41][42]; however, definitive evidence of the presence of alkyl adducts in the human stomach is still unavailable. The mutation spectrum of TP53 in understudied populations may encourage us to pursue the etiological varieties of GC in populations worldwide.…”

“…However, detailed information about the impact of these compounds as possible causes of GC has not yet been provided. Several mutagenic adenine modifications are known; some of them were detected in the gastric mucosa of human GC subjects [40][41][42]; however, the origins of exposure, the exact chemical process in human tissue, including the production of the intermediates, and the consequences presenting as mutation spectra have not been described yet.…”

Time-Course of Transcriptomic Change in the Lungs of F344 Rats Repeatedly Exposed to a Multiwalled Carbon Nanotube in a 2-Year Test

“…Therefore, future studies should examine the early genetic (and epigenetic) alterations in the lung during MWNT-7-induced lung cancer in rats and mice. DNA mutation signature analyses and adductome analysis will help to establish whether inflammation-related ROS actually does result in genomic damage during chronic MWCNT exposure [ 49 , 50 , 51 ].…”

Current and Future Methodology for Quantitation and Site-Specific Mapping the Location of DNA Adducts

“…For example, applying a nontargeted 'omics' approach, thousands of potential DNA adduct m/z features were observed in human tissues such as lung, bronchia, or saliva [97][98][99]. A challenging task will be to accurately identify the low abundant DNA adducts resulting from exogenous sources that are dwarfed by epigenetic marks and endogenous DNA adducts that are present at levels several orders of magnitude higher [100,101].…”