Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients Amr S. Soliman 1 * , Melissa Bondy 2 , Charity Renee Webb 3 , David Schottenfeld 1 , Joseph Bonner 1 , Nabih El-Ghawalby 4 , Ahmed Soultan 4 , Mohamed Abdel-Wahab 4 , Omar Fathy 4 , Gamal Ebidi 4 , Qing Zhang 2 , Joel K. Greenson 5 , James L. Abbruzzese 6 and Stanley R. Hamilton 3 1 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 2 Department of Epidemiology, Division of Cancer Prevention, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 3 Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 4 Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 5 Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 6 Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We stud- ied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5–8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras,G fi T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G fi C trans- version was detected in 26.9% of US tumors but none from Egypt (p 5 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G fi T transversion mutations and p53 exon 6 mutations were predicted by the coun- try of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancre- atic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences. ' 2006 Wiley-Liss, Inc. Key words: pancreatic cancer; molecular pathology; K-ras; p53; international differences Studies of unusual cancer distribution and analysis of particular genetic mutations may provide clues to cancer etiology. We previ- ously reported high incidence and mortality rates for colorectal carcinoma in young patients under age 40 in Egypt as compared to the United States. 1,2 We also reported patterns of genetic mutations in Egyptian colorectal cancers that were distinct from Western patients. 3 During our research on the epidemiology of colorectal cancer in Egypt, we observed an area in the northeast Nile River delta region with a high incidence of pancreatic cancer. 4 This region is known to have the highest environmental pollution of pesticides and heavy metals in Egypt. 5–9 Pancreatic cancer incidence rates vary considerably throughout the world, with the highest rates occurring in developed coun- tries. 10,11 This cancer shows a wide range of geographic incidence variation in the US with the Louisiana wetlands area and the Mississippi River delta regions reporting the highest rates. 12 Pancreatic cancer has not been widely reported in developing countries, except for the one area of high incidence we identified in the northeast Nile River delta region of Egypt. 4,13 The molecular genetics of pancreatic carcinoma have been stud- ied in detail. Mutations in the K-ras proto-oncogene and p53 gene are common, and Gadd45 mutations have been identified. 14 The study reported here was designed to evaluate the rates and types of these mutations in tumors from Egyptian patients who reside in the geographical region of extensive environmental pollution. The study also compared and contrasted the mutation characteristics with those of patients in the US. Material and methods This study included tumors obtained from surgically resected Stage II and III pancreatic cancer 15 patients in Egypt at the Gastro- intestinal Surgery Center (GSC) of Mansoura University and in the US at the University of Texas, M. D. Anderson Cancer Center in Houston. The group from Egypt included 44 newly diagnosed patients with histopathologically confirmed ductal adenocarci- noma of the pancreas. The Egyptian cases represent all consecu- tive patients undergoing resection of the pancreas who had prelim- inary histopathological diagnosis of pancreatic adenocarcinoma and confirmation of the diagnosis in Houston by one of the authors (SRH). All Egyptian patients were residents of the Dakahleia Province where the GSC is located, and no age or gender restric- tions were applied. The 44 Egyptian patients were all the patients who had surgical resections during the period of the study with re- cruitment from November 1998 to February 2000. These patients represented 26% of all incident pancreatic cancer patients seen at the study hospital during this period. This rate of histopatholgical confirmation in a developing country is lower than rates of histo- pathological confirmation in developed countries. 16 The second group of tumors was obtained as archival tissue from the surgical pathology files of 44 selected US patients who underwent diagnosis and treatment for adenocarcinoma with sur- gical resection of the pancreas between 1992 and 2004 at The Uni- versity of Texas, M. D. Anderson Cancer Center in Houston. Because of the young age of onset in Egyptian patients, the US cases were matched to the Egyptian patients as closely as possible by age (610 years) and gender. Matching was successful for 40 pairs of patients, and 4 US patients were matched for age, but not Grant sponsor: Eli Lilly Research; Grant sponsor: Topfer Research fund from M. D. Anderson; Grant sponsor: National Cancer Institute; Grant numbers: CA K07 090241, R03 CA099513-01; Grant sponsor: University of Michigan’s Cancer Center; Grant number: 5 P30 CA46592. *Correspondence to: Department of Epidemiology, School of Public Health, University of Michigan, 109 Observatory Road, Ann Arbor, MI 48109, USA. Fax: 1734-764-3192. E-mail: asoliman@umich.edu Received 20 September 2005; Accepted after revision 22 February 2006 DOI 10.1002/ijc.21986 Published online 17 April 2006 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 119, 1455–1461 (2006) ' 2006 Wiley-Liss, Inc. Publication of the International Union Against Cancer