The incidence of esophageal cancer is extremely high in Linxian County and certain other regions of the People's Republic of China. Epidemiologic and laboratory studies suggest that N-nitroso carcinogens and other environmental factors play a causative role. In the present study, employing over 100 DNA samples obtained from Lin-xian patients who underwent surgery for esophageal cancer, we have found a significant frequency of amplification of either the human epidermal growth factor receptor (HER-I) gene or the c-myc oncogene. These changes were found not only in tumor specimens, but also in adjacent non-tumor (grossly normal) tissue specimens obtained from patients with esophageal cancer. RNA samples were also obtained from over 30 tissue samples. These revealed considerable variation in the abundance of HER-I and c-myc transcripts in both the tumor and adjacent non-tumor specimens. A few samples revealed extremely high levels of these transcripts. Thus, changes in gene copy number or level of expression of HER-I or c-myc DNA sequences may play an important role in the pathogenesis of esophageal cancer in this high-risk region.
The ability to examine colonic effluents provides a powerful and convenient source of sampling and may be adapted for future large-scale screening.
Studies on the relevance of the N‐nitrosamines to esophageal cancer in China are reviewed. Esophageal cancer is a complex and multifactorial problem. Although a causal association between nitrosamines exposure and esophageal cancer in China has not yet been rigorously established, exposure of Lin‐Xian subjects to nitrosamines either directly or as a result of their in vivo formation has been detected in our study. Several N‐nitrosamines (NDMA, NDEA, NMBzA, NPyr, NPip, and NSAR) in gastric juice collected from Lin‐Xian inhabitants have been detected. A correlation was found between the lesions of esophageal epithelium and the amount of nitrosamines present. In addition, the amounts of N‐nitrosamino acids (N‐nitrosoproline, N‐nitrosothiazolidine 4‐carboxylic acid, NSAR, and nitrates) excreted in 24‐hr urine of subjects in Lin‐Xian were significantly higher than those in Fan‐Xian, indicating a higher exposure to N‐nitroso compound and their precursors of the inhabitants in the high‐risk area. The effect of nitrosamines on human esophagus has been investigated at the cellular levels. The amounts of O6‐MedG in DNA of esophageal or stomach mucosa of patients from Lin‐Xian were higher than that from Europe (Lyon and Essen). The presence of O6‐MedG in the human fetal esophagus cultured with NMBzA was also detected. These findings indicate that the elevated levels of O6‐MedG in esophageal DNA could be the result of a recent exposure to N‐nitroso compounds or a genetically determined reduced cellular capacity for repair of O6‐MedG from DNA. The hyperplasia was induced in the esophagus of human fetus that cultured with NMBzA for 2 weeks to 2 months. The intervention studies of esophageal cancer in Lin‐Xian have been pursured. Intake of moderate doses of ascorbic acids by Lin‐Xian subjects effectively reduced the urinary levels of N‐nitrosamino acids to those found in undosed subjects in the low‐risk area. If N‐nitroso compounds are formed in vivo and are among the causative factors of esophageal cancer in Lin‐Xian, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds. Thus, the plan of chemoprevention is carried out in Lin‐Xian.
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