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，人们一直对进一步了解其病因学知之甚少的罕见肿瘤抱有兴趣。目前，该项目主要集中在鼻咽癌、胆道癌和肝癌这四种肿瘤上。 鼻咽癌（NPC）具有非常明显的地理和种族分布，在人群中发病率很高。来自中国东南部的华裔人群的比例要低得多，而白人人群中的比例要低得多。虽然爱泼斯坦巴尔病毒（EBV）感染被认为是癌症发生所必需的，但其他遗传和外源因素也被认为很重要。为了调查与鼻咽癌病因相关的遗传、饮食、职业和行为因素，台湾进行了两项研究——一项针对约 1,000 名个体的病例对照研究和一项针对约 3,000 名个体（350 个家庭）的多重家庭研究。迄今为止，我们的结果表明风险与 CYP2E1 酶和几种 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。儿童期和断奶期间大量摄入亚硝胺和亚硝酸盐也与风险增加有关。职业接触木屑似乎也会影响风险；相反，甲醛暴露并不是一个重要的危险因素。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。对鼻咽肿瘤和正常细胞基因表达谱的评估表明，参与 DNA 修复和亚硝胺代谢的基因参与了鼻咽癌的发病机制。我们基于组织的表达研究的结果还表明 NPC 中 14 号染色体端粒末端杂合性丢失的可能性，并且 NPC 肿瘤细胞内的 EBV 基因表达影响参与免疫呈递的宿主基因的表达。这表明 EBV 能够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，来自多重 NPC 家族的 U 受影响个体的 EBV 抗体水平较高。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，正在进行对该人群的临床随访。全基因组筛查也在进行中，以评估与我们家族内 NPC 发育相关的染色体区域。 胆道癌是相对罕见但致命的恶性肿瘤。过去25年来，上海地区胆道癌的发病率增长速度超过任何其他恶性肿瘤。急剧上升的趋势表明危险因素的患病率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，我们对胆道癌进行了一项基于人群的跨学科研究。超过 3,000 名受试者参与了这项研究，其中包括 600 多名胆道癌患者、900 名胆结石患者以及从人群中随机选择的 1,000 名健康对照者。使用结构化调查问卷来获取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。该研究具有强大的生化和分子成分，收集了大量生物样本，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表明，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，胆道癌的过高风险与胆结石病史、慢性肝炎或肝硬化病史、胆结石家族史、产次（胆囊癌，仅限女性）、肥胖、食用腌制食品有关，以及胆囊炎或胰腺炎病史。相比之下，喝茶和服用阿司匹林可以降低风险，尤其是女性。乙型肝炎病毒的慢性携带者患胆管癌的风险是其两倍。脂质代谢、激素代谢、炎症和 DNA 修复途径中的许多基因变异，包括雌激素受体基因 (ER-α)、CYP17、载脂蛋白 E (APOE)、载脂蛋白 B (APOB)、低密度脂蛋白受体 (LDLR)、PTGS2、TNF、白细胞介素 8 (IL8)、IL8R 和 DNA 修复基因（XRCC3 和 MGMT84）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 (HCC) 和肝内胆管癌 (ICC) 两种主要组织学类型组成，是第六大最常见的癌症是世界上发生的癌症，也是癌症死亡的第三大常见原因。超过 80% 的肝癌发生在亚洲和撒哈拉以南非洲，但美国和欧洲等低发病率地区的发病率一直在上升。虽然乙型肝炎病毒和黄曲霉毒素摄入是高发地区肝癌的主要危险因素，但并非所有接触者都会患肝癌。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 的关联。在美国，我们的研究重点是确定与 HCC 和 ICC 发病率增加相关的因素。在记录关联研究中，我们发现乙型肝炎病毒、丙型肝炎病毒和糖尿病与HCC发病率增加有关，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类型肝癌风险的关系