Studies of Rare Cancers

罕见癌症的研究

• 批准号: 7330814
• 负责人: LOUISE BRINTON
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7330814
• 关键词: Studies; Rare; Cancers

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.

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，该计划主要集中在四种肿瘤上-鼻咽癌，胆管癌，肝癌和多发性骨髓瘤。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较高，而在白人中发病率要低得多。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。为了探讨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，我们的研究结果表明，风险和酶CYP 2 E1和几个DNA修复基因的特定变体，HLA和KIR基因的特定模式，以及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。在我们的家庭研究中发现的外源性危险因素与我们的病例对照研究中观察到的相似。从鼻咽肿瘤和正常细胞的基因表达谱的评估表明，基因参与DNA修复和亚硝胺的代谢参与鼻咽癌的发病机制。从我们的组织为基础的表达研究的结果也表明，在NPC染色体14的端粒末端的杂合性丢失的可能性，和NPC肿瘤细胞内的EBV基因表达影响宿主基因的表达参与免疫呈递。这可能是EBV逃避NPC免疫监视的一种机制。我们的研究表明，与普通人群相比，来自多重NPC家族的未受影响的个体具有升高的抗EBV抗体水平。为了评估这些抗EBV抗体水平升高的个体患NPC风险增加的可能性，正在对该人群进行临床随访。全基因组筛查也在进行中，以允许评估我们家族中与NPC发展相关的染色体区域。胆道癌是相对常见但致命的恶性肿瘤。近25年来，上海市胆道恶性肿瘤的发病率上升速度超过其他恶性肿瘤。这种急剧上升的趋势表明危险因素的流行或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。超过3,000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1,000名从人群中随机选择的健康对照。采用结构式问卷调查了解流行病学危险因素，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组成部分，广泛收集了生物样本，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，这三个亚基具有不同的分子变化，包括β-连环蛋白、p53、p16和K-ras的突变。