DNA Adductome Analysis Identifies N-Nitrosopiperidine Involved in the Etiology of Esophageal Cancer in Cixian, China

Abstract

Esophageal cancer is prevalent in Cixian, China, but the etiology of this disease remains largely unknown. Therefore, we explored this by conducting a DNA adductome analysis. Both tumorous and nontumorous tissues were collected from patients who underwent surgical procedures at Cixian Cancer Hospital and the Fourth Hospital of Hebei Medical University, which is in a low-incidence area. N 2-(3,4,5,6-Tetrahydro-2H-pyran-2-yl)­deoxyguanosine (THP-dG) was the major adduct detected in samples from esophageal cancer patients in Cixian. The precursor of THP-dG, N-nitrosopiperidine (NPIP), exhibited a strong mutagenic activity under metabolic activation in the Ames test and a significant dose-dependent increase in mutation frequency during an in vivo mutagenicity test with guanine phosphoribosyltransferase (gpt) delta rats. The NPIP-induced mutation was dominated by A:T to C:G transversions, followed by G:C to A:T and A:T to G:C transitions, in the liver and esophagus of animal samples. A similar mutational pattern was observed in the mutational signature of esophageal cancer patients that demonstrated weak correlation with THP-dG levels. These findings suggested that NPIP exposure is partly involved in the development of esophageal cancer in Cixian residents.

New horizons of DNA adductome for exploring environmental causes of cancer

“…Furthermore, we undertook whole-exome sequencing using samples from esophageal cancer patients living in the high-and low-incidence areas. 22 A nonnegative matrix factorization algorithm identified four types of mutational signatures ( Figure 5…”

“…Four mutational signatures were identified (A‐D). The illustration has been reproduced from Totsuka et al22 The horizontal axis represents the mutational types and the vertical axis indicates the percentage of mutations attributed to a specific signature. Each mutational signature is displayed on the basis of the trinucleotide frequency of the human genome.…”

“…Fewer HRAM‐adductome analyses are undertaken using human biological samples than those using cell lines or animal models. Thus, we carried out an HRAM‐adductome analysis to identify the environmental factors causing esophageal cancer in Cixian, an area well‐known for high incidence of this cancer type in China 22 . Nontumorous tissues were collected from esophageal cancer patients who underwent surgical procedures in the high‐ and low‐incidence (for comparison) areas.…”

“…The predominant mutations were A:T to C:G transversions, followed by G:C to A:T and A:T to G:C transitions. Furthermore, we undertook whole‐exome sequencing using samples from esophageal cancer patients living in the high‐ and low‐incidence areas 22 . A nonnegative matrix factorization algorithm identified four types of mutational signatures (Figure 5, A‐D); however, based on the contribution of each of these mutation signatures in individual samples, a clear separation was not observed between the high‐ and low‐incidence areas.…”

“…Thus, we carried out an HRAM-adductome analysis to identify the environmental factors causing esophageal cancer in Cixian, an area well-known for high incidence of this cancer type in China. 22 Nontumorous tissues were collected from esophageal cancer patients who underwent surgical procedures in the high-and low-incidence (for comparison) areas. Two-dimensional PCA indicated clear clustering in both areas, with several DNA adducts showing a greater contribution in the high-incidence area.…”