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，这一项目主要集中在四种肿瘤上--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学相关的遗传、饮食、职业和行为因素，在台湾进行了两项研究--一项约1,000人的病例对照研究和一项约3,000人(350个家庭)的多重家庭研究。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和KIR基因模式以及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与风险增加有关。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。在我们的家庭研究中发现的外源性危险因素与从我们的病例对照研究中观察到的相似。鼻咽癌和正常细胞的基因表达谱分析表明，参与DNA修复和亚硝胺代谢的基因参与了鼻咽癌的发病过程。我们的组织表达研究结果还表明，鼻咽癌中存在14号染色体端粒末端杂合性缺失的可能性，并且EBV基因在鼻咽癌细胞内的表达影响与免疫相关的宿主基因的表达。这提示了EBV逃避鼻咽癌免疫监视的可能机制。我们的研究表明，与普通人群相比，来自多个鼻咽癌家族的未受影响的个体的EBV抗体水平更高。为了评估这些EBV抗体水平升高的个体患鼻咽癌的风险增加的可能性，正在对这一人群进行临床随访。全基因组筛查也在进行中，以允许对我们家庭中与鼻咽癌发育有关的染色体区域进行评估。胆道癌是一种相对罕见但致命的恶性肿瘤。在过去的25年里，上海胆道癌的发病率比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，危险因素的患病率发生了变化，或者这些因素与遗传易感性之间的相互作用发生了变化。为了阐明这些因素，我们进行了一项基于人群的胆道癌跨学科研究。3000多名受试者参加了这项研究，其中包括600多名胆道癌患者、900名胆结石患者和从人群中随机选择的1000名健康对照。一个结构化的问卷被用来获得关于流行病学危险因素的信息，包括吸烟、饮酒、饮食、病史和生殖因素。这项研究有很强的生化和分子成分，收集了大量的生物样本，包括血清、DNA、胆结石、胆汁和组织样本。这项基于人群的研究的分子数据显示，这三个亚型具有明显的分子变化，包括β-连环蛋白、p53、p16和K-ras的突变。采访数据表明，胆道癌的高风险与胆结石病史、慢性肝炎或肝硬化史、胆结石家族史、产次(仅限女性胆囊癌)、肥胖、食用腌制食品以及胆囊炎或胰腺炎病史有关。相比之下，喝茶和服用阿司匹林与降低风险有关，特别是在女性中。慢性乙肝病毒携带者患胆道癌的风险是普通人的2倍。脂代谢、激素代谢、炎症和DNA修复途径中的一些基因变异，包括雌激素受体基因(ER-α)、细胞色素P17(CyP17)、载脂蛋白E(APOE)、载脂蛋白B(APOB)、低密度脂蛋白受体(LDLR)、Ptgs2、肿瘤坏死因子(TNF)、白介素8(IL8)、IL8R和DNA修复基因(XRCC3和MGMT84)的变异，与胆道癌，特别是胆管癌的风险增加有关。原发性肝癌由肝细胞癌和肝内胆管细胞癌两种主要组织学类型组成，是世界上第六大常见癌症和第三大常见致死原因。超过80%的肝癌发生在亚洲和撒哈拉以南非洲地区，尽管美国和欧洲等低发病率地区的发病率一直在上升。虽然乙肝病毒和黄曲霉毒素摄入是高发地区肝癌的主要危险因素，但并不是所有接触者都会患上肝癌。为了确定肝癌的其他危险因素，我们目前正在中国肝癌流行区研究有机氯农药和伏马菌素B1的相关性。在美国，我们的研究重点是确定与肝癌和肝细胞癌发病率增加相关的因素。在记录关联研究中，我们发现乙肝病毒、丙型肝炎病毒和糖尿病与肝细胞癌的发病率增加有关，而丙型肝炎病毒、人类免疫缺陷病毒、肝硬变和糖尿病与肝细胞癌的发病率增加有关。为了跟进这些发现，我们目前正在研究代谢综合征与这两种类型肝癌风险的关系。

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 four tumors--nasopharyngeal cancer, biliary cancer and liver cancer. 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, two studies were conducted in Taiwan - a case-control study of approximately 1,000 individuals and a multiplex family study of approximately 3,000 individuals (350 families). 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 KIR genes, 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. Exogenous risk factors identified within our family study were similar to those observed from our case-control study. Evaluation of gene expression profiles from nasopharynx tumor and normal cells suggest that genes involved in DNA repair and in the metabolism of nitrosamines are involved in NPC pathogenesis. Results from our tissue-based expression studies also suggest the possibility of loss-of-heterozygosity on the telomeric end of chromosome 14 in NPC, and that EBV gene expression within NPC tumor cells affect the expression of host genes involved in immune presentation. This suggests a possible mechanism by which EBV manages to evade immune surrveillance in NPC. Uaffected individuals from multiplex NPC families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To evaluate the possibility that these individuals with elevated levels of antibodies against EBV are at increased risk of NPC clinical follow-up of this population is underway. A genome-wide screen is also underway to permit an evaluation of chromosomal regions linked to NPC development within our families. Biliary tract cancers are relatively rare but fatal malignancies. 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 factor or interaction between these factors and genetic susceptibility. To elucidate these factors, we conducted a population-based interdisciplinary study of biliary tract cancer. More than 3,000 subjects were enrolled in the study, including over 600 biliary tract cancer patients, 900 gallstone patients, and 1,000 healthy controls randomly selected from the population. A structured questionnaire was used to elicit information on epidemiologic risk factors, including smoking, drinking, diet, medical history, and reproductive factors. The study had a strong biochemical and molecular component with an extensive collection of biological samples, including serum, DNA, gallstones, bile, and tissue samples. Molecular data from this population-based study show that these three subistes have distinct molecular changes, including mutations of beta-catenin, p53, p16, and K-ras. Interview data suggest that excess risks of biliary tract cancer were associated with a history of gallstones, a history of chronic hepatitis or liver cirrhosis, a family history of gallstones, parity (for gallbladder cancer, among women only), obesity, consumption of preserved foods, and a history of cholecystitis or pancreatitis. In contrast, tea drinking and aspirin use were associated with reduced risk, especially among women. Chronic carriers of the hepatitis B virus had a 2-fold risk of bile duct cancer. A number of variants of genes in the lipid metabolism, hormone metabolism, inflammation, and DNA repair pathways, including variants of the estrogen receptor gene (ER-alpha), CYP17, apolipoprotein E (APOE), apolipoprotein B (APOB), low-density lipoprotein receptor (LDLR), PTGS2, TNF, Inerleukin 8 (IL8), IL8R, and DNA repair genes (XRCC3 and MGMT84), were associated with an increased risk of biliary tract cancer, in particular bile duct cancer. Primary liver cancer, composed of two major histologic types, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the sixth most frequently occurring cancer in the world and the third most common cause of cancer mortality. Over 80% of liver cancers occur in Asia and sub-Saharan Africa, though incidence in low-rate areas, such as the U.S. and Europe, has been rising. While hepatitis B virus and aflatoxin consumption are major risk factors for HCC in high-rate areas, not all exposed persons develop HCC. In an effort to identify other risk factors for HCC, we are currently examining associations with organochlorine pesticides and fumonisin B1 in an HCC endemic area of China. In the U.S., our research has focused on identifying factors associated with the increase in incidence of both HCC and ICC. In record-linkage studies, we have found that hepatitis B virus, hepatitis C virus and diabetes are linked to the increasing incidence of HCC, while hepatitis C virus, human immunodeficiency virus, cirrhosis and diabetes are linked to the increasing incidence of ICC. To follow-up on these finding, we are currently examining the relationship of metabolic syndrome to risk of both types of liver cancer.