Studies of Rare Cancers

罕见癌症的研究

基本信息

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
项目类别：
财政年份：
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

项目摘要

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

长期以来，人们一直在对罕见肿瘤的进一步见解，这些肿瘤的病因知之甚少。目前，该项目将大多数努力集中在四个肿瘤上 - 咽癌，胆汁癌和肝癌。 鼻咽癌（NPC）具有非常独特的地理和种族分布，在中国东南部的中国人中以高率的中国人群和低率的速率发生。尽管人们认为对爱泼斯坦Barr病毒（EBV）的感染对于癌症的发展是必要的，但遗传和外源性的其他因素也被认为很重要。为了研究与NPC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 - 对大约1,000个个体的病例对照研究和大约3,000个个体（350个家庭）的多重家族研究。迄今为止，我们的结果表明，酶CYP2E1的风险与特定变体之间存在关联，以及几种DNA修复基因，HLA和KIR基因的特定模式以及长期吸烟。儿童期和断奶期间的硝基胺和亚硝酸盐的摄入量也与风险增加有关。对木尘的职业暴露似乎也影响了风险。相反，甲醛暴露不是重要的危险因素。我们家庭研究中发现的外源危险因素与我们的病例对照研究中观察到的危险因素相似。评估来自鼻咽肿瘤和正常细胞的基因表达谱，表明参与DNA修复和硝基胺代谢的基因参与NPC发病机理。我们基于组织的表达研究的结果还表明，NPC染色体14染色体端的杂合性丧失的可能性，NPC肿瘤细胞中的EBV基因表达会影响与免疫表现有关的宿主基因的表达。这表明EBV设法逃避了NPC中的免疫投降的可能机制。与普通人群相比，我们的研究中已经显示了来自多重NPC家族的未经无效的个体对EBV的抗体水平升高。为了评估这些对EBV抗体水平升高的人正在进行NPC临床随访的风险增加。还正在进行一个全基因组筛查，以评估与我们家族内NPC发展相关的染色体区域。 胆道癌是相对罕见但致命的恶性肿瘤。在过去的25年中，上海胆道癌的发病率比任何其他恶性肿瘤的发生率更快。急剧上升的趋势表明，这些因素与遗传敏感性之间的危险因素的流行或相互作用发生了变化。为了阐明这些因素，我们对胆道癌进行了基于人群的跨学科研究。这项研究招募了3,000多名受试者，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。一份结构化的问卷被用来获取有关流行病学风险因素的信息，包括吸烟，饮酒，饮食，病史和生殖因素。该研究具有强大的生化和分子成分，并具有广泛的生物样品，包括血清，DNA，胆结石，胆汁和组织样品。这项基于人群的研究的分子数据表明，这三个亚属性具有不同的分子变化，包括β-catenin，p53，p16和k-ras的突变。访谈数据表明，胆道癌的过多风险与胆结石的史，慢性肝炎或肝肝硬化史有关，胆结石的家族史，均等（仅在女性中，仅在女性中），肥胖症，保存的食物消耗以及胆囊炎或胆汁疾病的史。相比之下，饮酒和使用阿司匹林的使用量降低了风险，尤其是在女性中。丙型肝炎病毒的慢性载体患有胆管癌的2倍。脂质代谢，激素代谢，炎症和DNA修复途径中的许多变体，包括雌激素受体基因（ER-Alpha），CYP17，载脂蛋白E（APOE）E（APOE），载脂蛋白B（Apob），低密度脂蛋白受体（PTN）PTNRRRNR（PTN），PTN（PTN），PTN（apoB） Inerleukin 8（IL8），IL8R和DNA修复基因（XRCC3和MGMT84）与胆道癌的风险增加有关，尤其是胆管癌。 原发性肝癌，由两种主要的组织学类型组成，大多数组织学类型，大多数肝细胞癌（HCC）cholangactic cholangactic cholangatic（ICC）（ICC）（ICCARANCATTATS）（ICCARANCATATIC CHORANCATTATS）（ICCARCARCATTATS）soicarancarcarcarcarcarcarcArcAt。在世界上经常发生癌症，也是癌症死亡率的第三大最常见原因。超过80％的肝癌发生在亚洲和撒哈拉以南非洲，尽管在美国和欧洲等低利率地区的发病率正在上升。尽管乙型肝炎病毒和黄曲霉毒素的消耗是高速公路中HCC的主要危险因素，但并非所有暴露的人都会发展HCC。为了确定HCC的其他危险因素，我们目前正在研究中国HCC地方性地区与有机氯农药和富莫诺菌素B1的关联。在美国，我们的研究集中在确定与HCC和ICC发病率增加有关的因素。在记录连接研究中，我们发现乙型肝炎病毒，丙型肝炎病毒和糖尿病与HCC的发生率的增加有关，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两种肝癌风险的关系