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。到目前为止，我们的研究结果表明，风险与酶CYP2E1和几个DNA修复基因的特定变体，HLA的特定模式和长期吸烟之间存在关联。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。职业暴露于木尘似乎也会影响风险;相比之下，甲醛暴露不是一个重要的风险因素。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。初步结果似乎暗示了14号染色体的一个特定区域在该病病因中的重要性。 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，我们最近完成了一项以人群为基础的胆道癌跨学科研究的实地调查，这是有史以来规模最大、最全面的研究。该研究中收集的肿瘤组织的早期分子分析显示，几种基因突变的流行率，包括？连环蛋白、p53、p16和K-ras的表达因解剖学亚位点和组织学而异，提示胆道肿瘤的分子和致病途径可能因解剖学亚位点和组织学亚型而异。超过3,000名受试者参加了这项研究。该研究具有强大的生化和分子组成部分，广泛收集生物样本，包括血清，DNA，尿液样本，胆结石，胆汁和组织样本。生物样本的扩展收集、仔细收集的高质量暴露数据以及大规模研究将允许检验与胆道癌相关的许多紧急假设，包括螺杆菌S，伤寒和B型肝炎病毒（HBV）感染以及遗传因素。迄今为止，已经完成了一些初步分析，显示与胆结石相关的胆道癌风险较高，胆结石家族史，多产（仅胆囊癌），肥胖和胆囊炎或胰腺炎史;相反，喝茶与女性风险降低有关。慢性HBV感染也被发现与2倍的肝外胆管癌风险相关。 虽然在不发达国家中HCC的主要危险因素已得到很好的表征，但仍不清楚为什么一些高危人群会发生肿瘤，而另一些则不会。因此，我们正在中国的高危人群中进行研究，以检查饮食和环境暴露以及遗传易感性对HCC风险的影响。为了确定发达国家中与HCC风险增加相关的因素，我们正在丹麦和美国进行记录关联研究。这些研究可能有助于确定丙型肝炎病毒是否是导致HCC风险增加的原因，或者其他因素（如肥胖、糖尿病和脂肪肝）是否也会导致HCC风险增加。我们还在丹麦和美国进行了类似的CC记录连锁研究，因为CC的病因在这些地区基本上是未知的。此外，我们正在分析美国CC发病率的年龄-时期-队列模型，以确定增加的风险是否与队列效应比日历期效应更相关。

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 associted 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 linkage study is now under way in Taiwan to enable a careful and systematic assessment of genetic and environmental determinants of this cancer. Preliminary results appear to implicate the importance of a specific region of chromosome 14 in the etiology of the disease. 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 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 ?-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 anatomical subsite and histological subtype. More than 3,000 subjects were enrolled in the study. The study 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 extension collection of biological specimens, carefully collected high-quality exposure data, and the large size of the study will permit testing of a number of emergent hypothesis 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, 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. Although major risk factors for HCC in underdeveloped countries are well-characterized, it is still unclear why some high-risk persons develop tumors while others do not. Therefore, we are conducting studies in a high-risk population in China to examine the effects of dietary and environmental exposures, as well as genetic susceptibility on the risk of HCC. In an attempt to identify factors related to the increasing risk of HCC in the developed world, we are conducting record-linkage studies in Denmark and the U.S. 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. We also also conducting similar record-linkage studies of CC in Denmark and the U.S. as the etiology of CC is largely unknown in these areas. In addition, we are analyzing age-period-cohort models of CC 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.