Studies of Rare Cancers

长期以来，人们一直有兴趣进一步了解罕见肿瘤的病因，这些肿瘤的病因尚不清楚。目前，该项目主要集中在三种肿瘤上--鼻咽癌、胆道癌和肝癌。鼻咽癌具有非常明显的地理和种族分布，在中国东南部的华人中发病率很高，而在高加索人群中的发病率要低得多。虽然感染爱泼斯坦-巴尔病毒(EBV)被认为是癌症发生所必需的，但其他因素，包括遗传和外源性，也被认为是重要的。为了调查与鼻咽癌病因相关的遗传、饮食、职业和行为因素，在台湾进行了一项病例对照研究。到目前为止，我们的结果表明，风险与酶CYP2E1、人类白细胞抗原、吸烟和微量营养素的特定变异之间存在关联。在儿童时期和断奶期间摄入大量亚硝胺和亚硝酸盐也会增加风险。目前正在调查职业接触甲醛、溶剂、木尘和亚硝胺的情况。台湾目前正在进行一项大规模的连锁研究，以便对这种癌症的遗传和环境决定因素进行仔细和系统的评估。 在过去的25年里，胆道癌的发病率比上海其他任何恶性肿瘤都增长得更快。这种急剧上升的趋势表明，风险因素的流行程度发生了变化。为了阐明这些因素，我们即将完成一项大规模的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、烟酒使用、生殖因素和外源性激素的作用。在这项研究中有1000例癌症病例，将有足够的统计能力来分别检查每个子站点的病因。由于胆结石疾病倾向于在家族中聚集，因此将试图通过分析家族病史、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。肝癌的发病率具有显着的地域差异，绝大多数病例发生在东南亚和撒哈拉以南非洲地区。虽然这些地区的一些肝癌风险因素已经确定，但即使是高危人群，患肝癌的风险也不是均匀分布的。为了检验遗传易感性是否会影响风险，我们一直在与中国在海门市进行的一项大型前瞻性研究合作。在这一人群中，乙肝病毒感染和黄曲霉毒素暴露一直是主要的危险因素。嵌套式病例对照研究已经检查了黄曲霉毒素B1代谢途径(主要是GST和EPHX家族)中的基因座之间的变异，并发现了EPHX家族的变异可能对遗传易感性至关重要的证据。这些发现正在一项家庭分析中得到跟进，该分析包括病例对照先证者的一级和二级亲属。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)及其相关基因座对人群病毒状态和肝脏损害中间标志物的影响。关于接触有机氯、微囊藻毒素和伏马菌素的更新的分析正在计划之中。为了确定与西方化(如糖尿病和肥胖症)相关的医疗条件是否与肝癌的发生有关，我们正在进行一项记录关联病例对照研究，其中记录了住院记录中记录的先前医疗条件的信息。

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.