Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran Mohammad Reza Akbari 1,2 , Reza Malekzadeh 2 * , Dariush Nasrollahzadeh 2 , Dayan Amanian 2 , Ping Sun 3 , Farhad Islami 2 , Masoud Sotoudeh 2 , Shahriar Semnani 4 , Paolo Boffeta 5 , Sanford M. Dawsey 6 , Parviz Ghadirian 7 and Steven A. Narod 3 * 1 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada 2 Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran 3 Centre for Research in Women’s Health, University of Toronto, Toronto, Canada 4 Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Iran 5 International Agency for Research on Cancer, Lyon, France 6 Nutritional Epidemiology Branch, National Cancer Institute, USA 7 Department of Nutrition, University of Montreal, Montreal, Canada In northeastern Iran, there is an area of high incidence of esopha- geal cancer, which is populated by residents of Turkmen ancestry. Several environmental risk factors for esophageal cancer have been proposed, but the roles of familial and genetic factors have not been studied extensively in the Turkmen population. We eval- uated the importance of familial risk factors for esophageal cancer by performing a case–control study of 167 cases of esophageal squamous cell carcinoma and 200 controls of Turkmen ethnicity. Detailed family pedigrees of the cases and controls were con- structed, which documented all cancers in first- and second-degree relatives. The actuarial risk of cancer was then estimated in 2,097 first-degree relatives of cases and 2,783 first-degree relatives of the controls. A hazard ratio was constructed, based on a comparison of the 2 cumulative incidence curves. The risk to age 75 of esopha- geal cancer in the first-degree relatives of Turkmen patients with esophageal cancer was 34% versus 14% for the first-degree rela- tives of the controls (hazard ratio 5 2.3; p 5 3 3 10 28 ). Cases (9.6%) reported that their parents were related, versus 2.5% of the controls who reported this. (odds ratio 5 4.1; p value 5 0.006). Familial factors are important in the etiology of esophageal cancer among the Turkmen residents of Iran. The hazard ratio of 2.3 for cancer among first-degree relatives is consistent with an important contribution of heritable factors. It will be of interest to perform marker studies to establish which genes are responsible. ' 2006 Wiley-Liss, Inc. Key words: esophageal cancer; hereditary; familial; genetic; Turkmen; Iran Esophageal cancer is among the 10 most common malignancies worldwide, and ranks as the 6th leading cause of death from can- cer. 1 It constitutes 7% of all gastrointestinal (GI) cancers and is one of the most lethal of all cancers. 2,3 The incidence of esopha- geal cancer varies greatly between populations, with a greater than 50-fold difference observed between rates in high- and low-risk populations. 3 It is much more common in Asia than in western countries. The esophageal cancer belt is a geographic area of high incidence, which stretches from north-central China westward through Central Asia to northern Iran. 4,5 In Linxian, north of China, the annual incidence rate of esophageal cancer was 151/ 100,000 for males and 115/100,000 for females in the 1970s. 6 Far- ther west, in Gonbad, northeastern Iran, the annual incidence rate was reported to be 109/100,000 per year for men and 174/100,000 per year for women. 7,8 It seems that the incidence of esophageal cancer in Turkmen ethnicity is more than that in other inhabitants of this area. 7–9 The incidence rates in China and Iran appear to have decreased during the last 3 decades, but are still 100/ 100,000 per year for both males and females in these high inci- dence areas. 6,9,10 Gonbad is the second largest city of Golestan province in Iran and is located in the eastern semi-desert plain of the province. It is mainly populated by people of Turkmen ethnicity, who descended from the Oguz Turkic tribes who migrated from the Altai Moun- tains (on the border of China and Mongolia) to northern Iran. 11 Turkmen have oriental facial features and are believed to have a genetic background similar to that of East Asians. There are 2 main forms of esophageal cancer: squamous cell carcinoma and adenocarcinoma. More than 90% of all esophageal cancer cases in Iran are of the squamous cell type. 10 The principle risk factors for esophageal cancer are thought to be environmental. Two of the known risk factors are tobacco smoking and alcohol consumption. 2,3,12 However, alcohol is rarely consumed by men in Northeastern Iran, and neither risk factor is common among women. In this area in Iran, proposed risk factors include a dietary deficiency of fruits and vegetables, 13 the consumption of very hot beverages 13,14 and exposure to carcinogens due to opium con- sumption. 15–17 However, neither the relative risks associated with these factors nor their prevalence in the Iranian population are of sufficient magnitude to explain the extremely high incidence. It is therefore important that familial factors also be explored as possi- ble risk factors contributing to the development of squamous cell carcinoma of the esophagus in northeastern Iran. A central role for familial factors was suggested by the early observation of a family with 13 cases of esophageal cancer in a single village. 18 In a sub- sequent epidemiological study, Ghadirian et al. reported a positive family history of esophageal cancer in 47% of Turkmen patients with this disease. 19 The present study was undertaken to evaluate the existence of familial aggregation among esophageal cancer cases in northeastern of Iran and to quantify the risk associated with having an affected first-degree relative. Material and methods The city of Gonbad, the second major city of Golestan province, is located in the steppe grasslands of the Turkmen plain, in the easternmost district of the Caspian littoral in northeastern Iran. In August 2001, the Digestive Disease Research Center (DDRC) of Tehran University of Medical Sciences opened a referral clinic for upper GI tract cancers (the Atrak Clinic), where we presently con- duct a case–control study of upper GI malignancies. The clinic is located in Gonbad, at the largest hospital of eastern Golestan (the Khatam Hospital). The majority of cancer patients in this area first present to one of the local general practitioners, internists or sur- geons. Only a small number of patients are first diagnosed in cities outside of this area. More than 70% of the patients in the city and the surrounding rural area are referred to the Atrak Clinic in Kha- tam Hospital for the investigation of upper GI disorders. Grant sponsor: DDRC, NIH. *Correspondence to: Center for Research in Women’s Health, 7th Floor, 790 Bay Street, M5G 1N8 Toronto, Ontario, Canada. Fax: 11-416-351-3767. E-mail: steven.narod@sw.ca or Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, 14114 Tebran, Iran. Fax: 198-21-88012992. E-mail: malek@ams.ac.ir Received 15 September 2005; Accepted 28 November 2005 DOI 10.1002/ijc.21906 Published online 28 March 2006 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 119, 1047–1051 (2006) ' 2006 Wiley-Liss, Inc. Publication of the International Union Against Cancer