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鼻咽癌、胆道癌、肝癌和多发性骨髓瘤四种肿瘤上。鼻咽癌的地理和种族分布非常明显，在中国东南部的华人中发病率较高，在高加索人群中发病率较低。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。胆道癌是一种相对发病率较高但致命的恶性肿瘤。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。

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, liver cancer, and multiple myeloma.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 rate 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.