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和几个DNA修复基因的特定变异、特定的人类白细胞抗原模式和长期吸烟之间存在关联。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。职业接触木尘似乎也会影响风险；相比之下，甲醛暴露并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。初步结果似乎暗示了14号染色体特定区域在疾病病因中的重要性。 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，我们最近完成了一项基于人群的胆道癌跨学科研究的实地工作，这是有史以来规模最大、最全面的研究。研究中收集的肿瘤组织的早期分子分析显示，几种基因突变的发生率因解剖亚基和组织学的不同而不同，包括β-catenin、p53、p16和K-ras，这表明胆道肿瘤的分子和致病途径可能因解剖亚基和组织亚型而不同。3000多名受试者参加了这项研究。这项研究具有强大的生化和分子成分，收集了广泛的生物样本，包括血清、DNA、尿样、胆结石、胆汁和组织样本。生物标本的广泛收集，仔细收集的高质量暴露数据，以及大规模的研究将使一些与胆道癌有关的紧急假说得以检验，包括幽门螺杆菌、伤寒和乙肝病毒(乙肝)感染以及遗传因素。到目前为止，一些初步分析已经完成，显示与胆结石相关的胆道癌风险更高，胆结石家族史，多胎(仅适用于胆囊癌)，肥胖，以及胆囊炎或胰腺炎病史；相比之下，饮茶与女性的风险降低有关。乙肝病毒的慢性感染也被发现与患肝外胆管癌的风险增加了2倍。 尽管在不发达国家，肝癌的主要危险因素已经有了很好的描述，但仍然不清楚为什么一些高危人群会患上肿瘤，而另一些人则不会。因此，我们正在中国的一个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肝癌风险的影响。为了找出与发达国家肝癌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导致肝癌风险增加，或者是否有其他因素，如肥胖、糖尿病和脂肪肝疾病导致风险增加。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，以确定风险增加是否更多地与队列效应有关，而不是与日历周期效应有关。

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.