Esophageal cancer is the sixth most common cause of cancer death worldwide, killing over 380,000 people each year. Over 80% of esophageal cancers occur in developing countries, where the great majority of cases are squamous cell carcinomas. Esophageal cancer is characterized by striking geographic variation in incidence. One remarkable high-risk area, called the Central Asian Esophageal Cancer Belt, stretches from the Caspian Sea across Central Asia to northern China and includes focal areas with recorded incidence rates greater than 100/10(5)/ year in both genders. For the past 20 years, DCEG investigators have studied esophageal and gastric cancer in one of these extremely high-risk areas, Linxian, China, at the eastern end of the Belt. While these studies have discovered new risk factors for esophageal cancer in this region, they have produced an incomplete explanation of the etiology of this disease. The Investigators now have the opportunity to perform similar studies in another of these extremely high-risk areas, Golestan Province, Iran, at the other end of the high-risk Belt. The people of Golestan, in northeastern Iran, are geographically, culturally and ethnically quite different from the people of Linxian, and they appear to be similar only in their extraordinarily high rates of esophageal cancer. Performing similar studies in these two exceptional populations will give a better chance to identify important new modifiable risk factors for esophageal cancer in both places.

The proposed cohort study will be collaboration between the Digestive Disease Research Center of Tehran University of Medical Sciences (DDRC), the International Agency for Research on Cancer (IARC), and DCEG. The study will recruit 50,000 adults over four years in three administrative districts of eastern Golestan Province. Baseline assessments will include a lifestyle questionnaire, a semi-quantitative food frequency questionnaire, and collection of blood, hair, nails and urine. Follow-up will include active surveillance by a study team, aided by a comprehensive health network in the rural areas, a GI referral clinic in the largest town, and a provincial cancer registry. The main hypotheses include dietary hypotheses (low consumption of fruits and vegetables, high consumption of hot tea), exposure to potential carcinogens (tobacco, PAHs from non-tobacco sources), novel exposures (opium, animal contact), and genetic susceptibility. The feasibility of this study is demonstrated by the successful completion of a 1,000-person pilot study, the successful recruitment of the first 20,000 subjects in the proposed cohort by DDRC and IARC collaborators, and successful collaboration with the same DDRC and IARC collaborators in an ongoing case-control study and several smaller etiologic studies.