There has been a long-standing interest in gaining further insights into rare tumors whose etiology is poorly understood. At present, this project is focusing the majority of efforts on three tumors--nasopharyngeal, biliary and liver cancers. Nasopharyngeal cancer (NPC) has a very distinct geographic and ethnic distribution, occurring at high rates among ethnic Chinese from southeastern China and at much lower rates among Caucasian populations. While infection with the Epstein Barr virus (EBV) is believed to be necessary for development of the cancer, other factors, both genetic and exogenous, are also thought to be important. To investigate genetic, dietary, occupational, and behavioral factors related to the etiology of NPC, a case-control study was conducted in Taiwan. To date, our results suggest an association between risk and specific variants of the enzyme CYP2E1 and several DNA repair genes, specific patterns of HLA, and long-term cigarette smoking. High intakes of nitrosamines and nitrite during childhood and weaning also were associated with increased risks. Occupational exposures to wood dusts also appeared to affect risk; in contrast, formaldehyde exposure was not a significant risk factor. A large-scale family (linkage) study is ongoing in Taiwan to enable a careful and systematic assessment of genetic and environmental determinants of this cancer. A genome-wide screen conducted within our family study indicated the importance of a specific region of chromosome 14 in the etiology of the disease. Results from our efforts also indicate that unaffected family members from our high-risk families have elevated levels of antibodies against EBV compared to the general population, suggesting the possibility that these individuals are at increased risk of NPC. During the last 25 years, the incidence of biliary tract cancer in Shanghai has increased more rapidly than that of any other malignancy. The sharply rising trend suggests a change in the prevalence of risk factors. To elucidate these factors, we recently completed fieldwork for a population-based interdisciplinary study of biliary tract cancer, the largest and most comprehensive ever. Earlier molecular analyses from tumor tissue collected in the study showed that the prevalence of mutations of several genes, including Beta-catenin, p53, p16, and K-ras, varies by anatomic subsite and histology, suggesting that the molecular and causal pathways of biliary tract neoplasms may differ by anatomic subsite and histological subtype. More than 3,000 subjects were enrolled in the study, which has a strong biochemical and molecular component with an extensive collection of biological samples, including serum, DNA, urine samples, gallstones, bile, and tissue samples. The extensive collection of biological specimens, the carefully collected high-quality exposure data, and the large size of the study will permit testing of a number of emergent hypotheses related to biliary tract cancer, including Helicobacter S., infection with typhoid fever and hepatitis B virus (HBV), and genetic factors. To date, a number of initial analyses have been completed, showing higher risks of biliary tract cancers associated with gallstones, a family history of gallstones, multiparity (for gallbladder cancer only), obesity, consumption of preserved foods, and a history of cholecystitis or pancreatitis; in contrast, tea drinking is associated with reduced risk among women. Chronic infection with HBV has also been found to be associated with a 2-fold risk of extrahepatic bile duct cancer. Certain markers of genetic susceptibility, including variants of the estrogen receptor gene, DNA repair genes (XRCC3 and MGMT84), apolipoprotein E, and low-density lipoprotein receptor (LDLR) genes, are associated with increased risk of biliary tract cancer. Primary liver caner is one of the most common cancers in the world, but mainly occurs in Asia and sub-Saharan Africa. In these high-risk regions, major risk factors have been identified. It is unclear, however, why some persons exposed to these factors develop tumors while others do not. Therefore, we are conducting studies in high-risk populations of China to examine the effects of dietary and environmental exposures, as well as genetic susceptibility, on the risk of liver cancer. In lower risk regions of the world, the incidence of liver cancer has been increasing. To examine factors related to the rise in incidence, we are conducting record-linkage studies in Denmark and the U.S. These studies are examining the risks of both hepatocellular carcinoma (the major type of liver cancer) and intrahepatic cholangiocarcinoma (the second most common type of liver cancer) These studies may help to determine whether hepatitis C virus is responsible for the increasing rates or whether other factors, such as obesity, diabetes mellitus and fatty liver disease are contributing to risk. In addition, we are analyzing age-period-cohort models of liver cancer incidence rates in the U.S. to determine whether the increased risk is more related to a cohort effect than to a calendar period effect and to examine whether the patterns are similar between hepatocellular carcinoma and intrahepatic cholangiocarcinoma.