Studies of Rare Cancers

罕见癌症的研究

• 批准号: 7593192
• 负责人: LOUISE BRINTON
• 金额: $ 139.39万
• 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/7593192
• 关键词: Affect; Aflatoxins; Africa South of the Sahara; Antibodies; Apolipoprotein E; Apolipoproteins B; Area; Asia; Aspirin; Behavioral; Bile duct carcinoma; Bile fluid; Biliary Tract Cancer; Biliary calculi; Biochemical; Biological; CYP17A1 gene; CYP2E1 gene; Cancer Etiology; Cancer Family; Cancer Patient; Case-Control Studies; Caucasians; Caucasoid Race; Childhood; China; Chinese People; Cholangiocarcinoma; Cholecystitis; Cholelithiasis; Chromosomes, Human, Pair 14; Chronic; Chronic Hepatitis; Cirrhosis; Clinical; Collection; Consumption; DNA; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Data Linkages; Development; Diabetes Mellitus; Diet; Disease; Dust; Enrollment; Enzymes; Estrogen Receptors; Etiology; Europe; Evaluation; Exposure to; Family; Family Study; Family history of; Formaldehyde; Fumonisin B1; Gallbladder Carcinoma; Gene Expression; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; HIV; Hepatitis B Virus; Hepatitis C virus; Histologic; Human Herpesvirus 4; Immune; Incidence; Individual; Infection; Inflammation; Intake; Interdisciplinary Study; International; Interview; Intrahepatic Cholangiocarcinoma; Investigation; Link; Liver Cirrhosis; Loss of Heterozygosity; Low Density Lipoprotein Receptor; Malignant Neoplasms; Malignant neoplasm of gallbladder; Malignant neoplasm of liver; Malignant neoplasm of nasopharynx; Medical History; Metabolic syndrome; Molecular; Molecular Profiling; Mutation; Nasopharyngeal Neoplasms; Nitrites; Nitrosamine Metabolism; Nitrosamines; Normal Cell; Numbers; Obesity; Occupational; Occupational Exposure; PTGS2 gene; Pancreatitis; Pathogenesis; Patients; Pattern; Persons; Population; Preserved Foods; Prevalence; Primary carcinoma of the liver cells; Questionnaires; Rate; Receptor Gene; Recording of previous events; Reproductive History; Research; Risk; Risk Factors; Sampling; Serum; Smoking; Structure; TNF gene; TP53 gene; Taiwan; Tea; Thinking; Tissue Sample; Tissues; Variant; Weaning; Woman; Wood material; base; beta catenin; cancer risk; cigarette smoking; cyclooxygenase 2; drinking; follow-up; hormone metabolism; human ESR1 protein; insight; interest; lipid metabolism; mortality; neoplastic cell; organochlorine pesticide; parity; trend; tumor

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.<BR><BR>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.<BR><BR>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.<BR><BR>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

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、胆管癌和肝癌四种肿瘤上。<BR><BR>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。全基因组筛查也正在进行中，以评估与我们家庭内NPC发展相关的染色体区域。<BR><BR>胆道癌是相对罕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。访谈数据表明，胆道癌的额外风险与胆结石史、慢性肝炎或肝硬化史、胆结石家族史、产次（胆囊癌仅限于女性）、肥胖、食用腌制食品以及胆囊炎或胰腺炎史相关。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B型肝炎病毒携带者患胆管癌的风险是正常人的2倍。脂质代谢、激素代谢、炎症和DNA修复途径中的许多基因变体，包括雌激素受体基因的变体（ER-α）、CYP 17、载脂蛋白E（APOE）、载脂蛋白B（APOB）、低密度脂蛋白受体（LDLR）、PTGS 2、TNF、白细胞介素8（IL 8）、IL 8 R和DNA修复基因（XRCC 3和MGMT 84）与胆道癌，特别是胆管癌的风险增加有关。<BR><BR>原发性肝癌由两种主要的组织学类型肝细胞癌（HCC）和肝内胆管细胞癌（ICC）组成，是世界上第六大最常见的癌症和第三大最常见的癌症死亡原因。 超过80%的肝癌发生在亚洲和撒哈拉以南非洲，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B型肝炎病毒和黄曲霉毒素消费是肝癌高发地区的主要危险因素，但并非所有接触者都会发展为肝癌。 为了确定HCC的其他危险因素，我们目前正在中国HCC流行区研究有机氯农药和伏马菌素B1的相关性。 在美国，我们的研究集中于确定与HCC和ICC发病率增加相关的因素。 在记录关联研究中，我们发现B型肝炎病毒、丙型肝炎病毒和糖尿病与HCC发病率的增加有关，而丙型肝炎病毒、人类免疫缺陷病毒、肝硬化和糖尿病与ICC发病率的增加有关。 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