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Esophageal squamous cell carcinoma (ESCC) accounts for about 90% of the 456,000 incident esophageal cancers each year. Regions of high incidence include Eastern to Central Asia, along the Rift Valley in East Africa, and into South Africa. There are many causes of ESCC, which vary among regions. Early studies in France associated smoking cigarettes and heavy alcohol consumption with high rates of ESCC, but these factors cannot explain the high incidence in other regions. We discuss other risk factors for ESCC, including polycyclic aromatic hydrocarbons from a variety of sources, high-temperature foods, diet, and oral health and the microbiome-all require further research. A growing list of defined genomic regions affects susceptibility, but large genome-wide association studies have been conducted with ethnic Chinese subjects only; more studies are called for in the rest of Asia and Africa. ESCC has been understudied, but growing infrastructure in more high-incidence countries will allow rapid progress in our understanding.

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Esophageal cancer incidence and mortality rates in Linxian, China are among the highest in the world. We examined risk factors for esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC), and gastric noncardia cancer (GNCC) in a populationbased, prospective study of 29,584 adults who participated in the Linxian General Population Trial. All study participants completed a baseline questionnaire that included questions on demographic characteristics, personal and family history of disease, and lifestyle factors. After 15 years of follow-up, a total of 3,410 incident upper gastrointestinal cancers were identified, including 1,958 ESCC, 1,089 GCC and 363 GNCC. Cox proportional hazard models were used to estimate risks. Increased age and a positive family history of esophageal cancer (including ESCC or GCC) were significantly associated with risk at all 3 cancer sites. Additional risk factors for ESCC included being born in Linxian, increased height, cigarette smoking and pipe smoking; for GCC, male gender, consumption of moldy breads and pipe smoking; and for GNCC, male gender and cigarette smoking. Protective factors for ESCC included formal education, water piped into the home, increased consumption of meat, eggs and fresh fruits and increased BMI; for GCC, formal education, water piped into the home, increased consumption of eggs and fresh fruits and alcohol consumption; and for GNCC, increased weight and BMI. General socioeconomic status (SES) is a common denominator in many of these factors and improving SES is a promising approach for reducing the tremendous burden of upper gastrointestinal cancers in Linxian.Key words: gastric cardia cancer; gastric noncardia cancer; cohort studies; diet; smoking Esophageal cancer is the sixth most common cause of cancerrelated death worldwide. 1 Some of the world's highest incidence and mortality rates of esophageal cancer occur in China. 2,3 Considerable geographic variation exists in these rates across the country, with the most prominent cluster seen in North Central China, particularly in Lin county (Linxian). 3,4 Esophageal cancer mortality rates in Linxian exceed the Chinese average rates by 10-fold and the rates among Caucasian Americans by 100-fold. 5 In Linxian, esophageal squamous cell carcinoma and gastric cardia cancer are both frequent and have traditionally been considered a single disease, esophageal cancer, because of their similar symptoms. Reasons for the unusually high rates of esophageal and gastric cardia cancers in the Linxian population are unclear, but recent reports suggest that rates have begun to decline. 6 Although tobacco smoking and alcohol drinking account for over 90% of esophageal squamous cell carcinoma in the West, 7,8 previous studies have shown that they are not important contributing factors to the development of cancer in Linxian. 9,10 The geographic variation in occurrence in China strongly suggests that environmental or lifestyle factors are major contributors to the etiology of esophageal/gastric cardia cancer. Diet ha...