The etiology of esophageal cancer in high- and low- risk areas of Jiangsu province, China

[Background]Esophageal cancer (EC) remains one of the most common and fatal malignancies worldwide. The geographic variation in EC occurrence is striking, and China is an area with one of the highest incidences of EC. A number of epidemiological studies have been conducted toward EC in the past decades, results suggested that tobacco smoking, alcohol drinking, unhealthy dietary factors and chronic injuries of the esophageal mucosa are important in the development of this disease. Genetic polymorphisms in enzymes involved in metabolism of carcinogens may also influence individual susceptibility. However, the effects of major lifestyle and hereditary risk factors on the development of EC remain poorly understood in China. Moreover, little attention has been paid to the etiological heterogeneity between similar areas with great risk gradient. [Methods]From 2003 to 2007, a large population-based case-control study of EC has been conducted in a selected high-risk area and a selected low-risk area of Jiangsu Province, one of the highest cancer incidence areas in China. In total, 1,520 cases and 3,879 controls were recruited. In this thesis, we evaluated the role of major lifestyle factors such as tobacco smoking, alcohol drinking and dietary factors, as well as inherited determinants including family history of cancer and genetic polymorphisms of alcohol-metabolizing related genes on the risk of EC. In addition, we investigated how much of the risk gradient between two areas could be explained by variation in the distributions of major risk factors. [Results] Tobacco smoking and alcohol drinking moderately increased the risk of EC, while the positive associations were only found among men but not among women. Dietary factors were observed to play important roles in the development of EC. Specific dietary habits i.e., fast eating speed, and hot eating and/or drinking substantially elevated EC risk and could explain more than 20% of EC cases each. High intake of salty foods and fried foods, low consumption of raw garlic were also observed to increase the risk of EC. In addition to environmental and lifestyle factors, we confirmed that a positive family history can significantly increase EC risk, and found the inheritance may modify the effect of some unhealthy lifestyles. Moreover, we further explored the relationship between EC and single nucleotide polymorphismsof ADH1B, ADH1C and ALDH2 genes. Results showed that the slow metabolizing ADH1B G allele, ADH1C G allele and ALDH2 A allele significantly increased EC risk among moderate-to-heavy alcohol drinkers, and a significant interaction was observed between ALDH2 gene and alcohol consumption. Lastly, we found that more than 60% of EC cases could be attributable to major lifestyle risk factors in the study population; furthermore, dissimilar distribution of several lifestyle factors, together with variations of hereditary factors may be largely responsible for the incidence difference between two study areas. [Conclusion]The findings in this thesis confirm that unhealthy lifestyles including smoking, alcohol drinking and some dietary factors are the predominant risk factors of EC in China, and a large proportion of incidence difference between regions at varying risk could be attributed to the different prevalence of lifestyle factors. As most of the identified risk factors are modifiable, these could be translated into risk reduction prevention programs in China, and a substantial proportion of new EC cases are expected to be prevented by eliminating or avoiding these risk factors in the population.