Studies of Rare Cancers

长期以来，人们一直有兴趣进一步了解病因学知之甚少的罕见肿瘤。目前，该项目主要集中在鼻咽癌、胆管癌和肝癌三种肿瘤上。 鼻咽癌（NPC）具有非常独特的地理和种族分布，在中国东南部的华人中发病率很高，而在高加索人群中发病率要低得多。虽然爱泼斯坦巴尔病毒（EBV）感染被认为是癌症发展所必需的，但其他遗传和外源因素也被认为是重要的。为探讨遗传、饮食、职业及行为等因素与鼻咽癌之相关性，本研究在台湾进行病例对照研究。迄今为止，我们的研究结果表明，风险与酶CYP2E1，HLA，吸烟和微量营养素的特定变体之间存在关联。儿童期和断奶期摄入大量亚硝胺和亚硝酸盐也与风险增加有关。目前正在调查甲醛、溶剂、木屑和亚硝胺的职业暴露。台湾目前正在进行一项大规模的连锁研究，以便能够仔细和系统地评估这种癌症的遗传和环境决定因素。 近25年来，上海市胆道恶性肿瘤发病率上升速度居恶性肿瘤之首。急剧上升的趋势表明危险因素的普遍性发生了变化。为了阐明这些因素，我们即将完成一项大规模基于人群的病例对照研究，以调查胆结石、胆道细菌感染、饮食因素、肥胖、吸烟和饮酒、生殖因素和外源性激素的作用。研究中有1，000例癌症病例，将有足够的统计功效来检查每个子部位的病因。由于胆结石病倾向于在家族中聚集，因此将尝试通过分析家族史和检测易感基因的多态性以及与生活方式因素的相互作用来评估遗传易感性是否在胆道癌中起作用。 肝癌的发病率具有惊人的地理差异性，绝大多数病例发生在东南亚和撒哈拉以南非洲。虽然这些地区肝癌的一些风险因素已经确定，但即使是高风险个体，患肝癌的风险也不是均匀分布的。为了研究遗传易感性是否影响风险，我们一直在与中国海门市进行的一项大型前瞻性研究合作。在这一人群中，B型肝炎病毒感染和黄曲霉毒素暴露是主要的危险因素。巢式病例对照研究检查了黄曲霉毒素B1代谢途径（主要是GST和EPHX家族）中基因座的变异，并发现EPHX家族中的变异可能对遗传易感性至关重要的证据。这些发现正在一项包括病例对照先证者的一级和二级亲属的家族分析中进行随访。此外，我们正在前瞻性地研究同型半胱氨酸和B族维生素（叶酸、维生素B6、维生素B12）及其相关遗传基因座对人群病毒状态和肝损伤中间标志物的影响。目前正在计划对接触有机氯、微囊藻毒素和伏马菌素进行更多新的分析。为了确定与西化相关的医学状况（例如，糖尿病和肥胖症）与肝癌的发展有关，我们正在进行一项记录联系病例对照研究，在这项研究中，正在查阅住院记录中记录的以前医疗状况的信息。

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, HLA, smoking and micronutrients. High intakes of nitrosamines and nitrite during childhood and weaning also were associted with increased risks. Occupational exposures to formaldehyde, solvents, wood dusts, and nitrosamines are currently under investigation. A large-scale linkage study is now under way in Taiwan to enable a careful and systematic assessment of genetic and environmental determinants of this cancer. During the last 25 years, biliary tract cancer incidence has increased more rapidly than any other malignancy in Shanghai. The sharply rising trend suggests a change in the prevalence of risk factors. To elucidate these factors, we are nearing completion of a large scale population-based case-control study to investigate the role of gallstone, bacterial infections of the biliary tract, dietary factors, obesity, use of tobacco and alcohol, reproductive factors, and exogenous hormones. With 1,000 cancer cases in the study, there will be sufficient statistical power to examine the etiology separate for each subsite. Since gallstone disease tends to cluster in families, attempts will be made to evaluate whether genetic predisposition plays a role in biliary tract cancer, through analysis of family history and testing for polymorphisms of susceptibility genes as well as interactions with lifestyle factors. The incidence of liver cancer has striking geographic variability with the vast majority of cases arising in southeast Asia and sub-Saharan Africa. While some risk factors for liver cancer in these areas are well established, the risk of developing liver cancer is not uniformly distributed among even high-risk individuals. To examine whether genetic susceptibility influences risk, we have been collaborating with a large prospective study being conducted in Haimen City, China. In this population, hepatitis B virus infection and aflatoxin exposure have been the major risk factors. Nested case-control investigations have examined variants among loci that are in the aflatoxin B1 metabolism pathway (primarily the GST and EPHX families) and have found evidence that variants in the EPHX family may be critical to genetic susceptibility. These findings are being followed up in a family analysis that includes the first and second degree relatives of the case-control probands. In addition, we are prospectively examining the effect of homocysteine and B vitamins (folate, vitamin B6, vitamin B12) and their related genetic loci on viral status of the population and intermediate markers of liver damage. More novel analyses of exposure to organochlorines, microcystins and fumonisins are being planned. In an effort to determine whether medical conditions associated with westernization (e.g., diabetes and obesity) are related to the development of liver cancer, we are conducting a record linkage case-control study in which information on prior medical conditions as recorded in inpatient records is being accessed.