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Studies of Rare Cancers

罕见癌症的研究

基本信息

批准号：
7966658
负责人：
LOUISE BRINTON
金额：
$ 153.73万
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/7966658
关键词：
Affect Africa South of the Sahara African American Antibodies Anus Apolipoprotein E Apolipoproteins B Area Asia Aspirin Behavioral Bile duct carcinoma Bile fluid Biliary Tract Cancer Biochemical Biological Biopsy CAG repeat CYP17A1 gene CYP2E1 gene California 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 Clinic Clinical Cohort Studies Collection Colposcopy Consumption DNA DNA Repair DNA Repair Gene DNA Repair Pathway Data Data Linkages Databases Developed Countries Developing Countries Development Diabetes Mellitus Diagnostic Procedure Diet Disease Dust Enrollment Enzymes Epididymitis Estrogen Receptors Etiology Europe Evaluation Exposure to Family Family Study Family history of Female Formaldehyde Fracture Fumonisin B1 Gene Expression General Population Genes Genetic Genetic Markers Genetic Predisposition to Disease Genetic Variation Gynecomastia HBV and Aflatoxin HIV Hepatitis B Virus Hepatitis C virus Histologic Hormones Hospitalization Human Herpesvirus 4 Human Papillomavirus Immune Incidence Individual Infection Inflammation Intake Interdisciplinary Study International Interview Intrahepatic Cholangiocarcinoma Investigation Klinefelter&apos s Syndrome Life Link Liver Cirrhosis Loss of Heterozygosity Low Density Lipoprotein Receptor Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Malignant neoplasm of gallbladder Malignant neoplasm of liver Malignant neoplasm of male breast Malignant neoplasm of nasopharynx Medical Medical History Metabolic syndrome Methods Modality Molecular Molecular Profiling Morbidity - disease rate Mutation Nasopharyngeal Neoplasms Natural History Nitrites Nitrosamine Metabolism Nitrosamines Normal Cell Obesity Occupational Occupational Exposure Orchitis PTGS2 gene Pancreatitis Pathogenesis Patients Pattern Persons Population Preserved Foods Prevalence Primary carcinoma of the liver cells Questionnaires Receptor Gene Recording of previous events Relative (related person)Reproductive History Research Resort Risk Risk Factors Sampling Screening procedure Serum Smoking Structure TNF gene TP53 gene Taiwan Tea Testing Tissue Sample Tissues United States Department of Veterans Affairs Variant Weaning Woman Wood material base beta catenin cancer risk care systems case control cigarette smoking cohort computerized drinking follow-up genome wide association study hormone metabolism human ESR1 protein insight interest lipid metabolism malignant breast neoplasm men who have sex with men mortality neoplastic cell organochlorine pesticide parity population based 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 and diabetes was associated with a 2-fold risk of gallbladder stones and gallbladder 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, AR CAG repeats, 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. We have recently extended our interests in the etiology of breast cancer to also include a focus on rarely occurring male breast cancers. In an analysis within the large NIH-AARP cohort study, we identified that a family history of breast cancer in a female relative, obesity, physical inactivity and a history of bone fractures related to increased risk. An investigation within the U.S. Veterans Affairs computerized medical care system database found increased risks of male breast cancer associated with hospitalizations for Klinefelter syndrome, obesity, diabetes, gynecomastia, orchitis/epididymitis and cholelithiasis (latter only among African Americans). We are currently following up these findings in a pooled analysis in which we hope to include data from the majority of case-control and cohort investigations. Cohort investigations will be particularly valuable towards assessing relationships with genetic markers and endogenous hormones. Human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) are at a risk of anal cancer that approaches the risk of cervical cancer for unscreened women living in developing countries. There is currently no accepted method for screening HIV-positive MSM for anal precancer to reduce the morbidity and mortality due to anal cancer; in the absence of a standard and effective screening modality, clinics often resort to anoscopy, a diagnostic procedure akin to colposcopy, and directed biopsies on all HIV-positive MSM. At Kaiser Permanente Northern California, we are enrolling 1,000 HIV-positive MSM in a 2-year study to describe the natural history of HPV and evaluate the clinical utility of various tests to detect prevalent, 1-year cumulative, and 2-year cumulative anal precancer and cancer.

长期以来，人们一直有兴趣进一步了解病因不明的罕见肿瘤。目前，该项目主要集中在鼻咽癌、胆道癌和肝癌四种肿瘤上。鼻咽癌（NPC）具有非常明显的地理和种族分布，在中国东南部华人中发病率高，而在高加索人群中发病率低得多。虽然感染eb病毒（EBV）被认为是癌症发展的必要条件，但其他因素，包括遗传和外源性因素，也被认为是重要的。为了研究与鼻咽癌病因相关的遗传、饮食、职业和行为因素，我们在台湾进行了两项研究——一项约1000人的病例对照研究和一项约3000人（350个家庭）的多重家庭研究。迄今为止，我们的研究结果表明，风险与CYP2E1酶和几种DNA修复基因的特定变异、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我们的病例对照研究中观察到的相似。对鼻咽癌和正常细胞基因表达谱的分析表明，参与DNA修复和亚硝胺代谢的基因参与了鼻咽癌的发病机制。我们基于组织的表达研究结果还表明，鼻咽癌14号染色体端粒端杂合性缺失的可能性，以及鼻咽癌肿瘤细胞内EBV基因的表达影响参与免疫呈递的宿主基因的表达。这提示EBV在NPC中设法逃避免疫监视的可能机制。我们的研究显示，与一般人群相比，来自多重NPC家族的未受影响个体的EBV抗体水平升高。为了评估这些EBV抗体水平升高的个体患鼻咽癌风险增加的可能性，正在对该人群进行临床随访。全基因组筛选也正在进行中，以便评估与我们家族中NPC发展相关的染色体区域。胆道肿瘤是一种相对罕见但致命的恶性肿瘤。在过去的25年里，胆道癌在上海的发病率比其他任何恶性肿瘤的发病率增长都要快。这种急剧上升的趋势表明，危险因素的流行程度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，我们进行了一项以人群为基础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多名胆道癌症患者，900名胆结石患者，以及从人群中随机选择的1000名健康对照者。采用结构化问卷调查的方式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。该研究具有很强的生化和分子成分，收集了广泛的生物样本，包括血清、DNA、胆结石、胆汁和组织样本。这项以人群为基础的研究的分子数据显示，这三种亚种具有不同的分子变化，包括β -连环蛋白、p53、p16和K-ras的突变。访谈数据显示，胆道癌的过度风险与胆结石史、慢性肝炎或肝硬化史、胆结石家族史、胎次（胆囊癌，仅限女性）、肥胖、食用腌制食品、胆囊炎或胰腺炎史有关。相比之下，喝茶和服用阿司匹林与降低风险有关，尤其是在女性中。慢性乙肝病毒携带者患胆管癌的风险是前者的2倍，糖尿病患者患胆囊结石和胆囊癌的风险是后者的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、白介素8 （IL8）、IL8R、AR CAG重复序列和DNA修复基因（XRCC3和MGMT84）的变异，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，是世界上第六大常见癌症，也是第三大常见癌症死亡原因。超过80%的肝癌发生在亚洲和撒哈拉以南非洲地区，不过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的摄入是HCC高发地区的主要危险因素，但并非所有暴露者都发展为HCC。为了确定HCC的其他危险因素，我们目前正在中国HCC流行地区研究有机氯农药和伏马菌素B1的关系。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。为了进一步研究这些发现，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。我们最近扩展了我们对乳腺癌病因学的兴趣，也包括对罕见的男性乳腺癌的关注。在美国国立卫生研究院和美国退休人员协会的一项大型队列研究中，我们发现，女性亲属的乳腺癌家族史、肥胖、缺乏运动和骨折史与风险增加有关。美国退伍军人事务部计算机化医疗保健系统数据库的一项调查发现，男性乳腺癌的风险增加与Klinefelter综合征、肥胖、糖尿病、男性乳房发育症、睾丸炎/附睾炎和胆石症（后者仅在非裔美国人中）住院有关。我们目前正在对这些发现进行汇总分析，我们希望纳入大多数病例对照和队列调查的数据。队列调查对于评估与遗传标记和内源性激素的关系将特别有价值。人类免疫缺陷病毒（HIV）阳性的男男性行为者（MSM）患肛门癌的风险接近发展中国家未接受筛查的妇女患宫颈癌的风险。目前还没有公认的方法来筛查艾滋病毒阳性的男男性行为者的肛门癌前病变，以减少肛门癌的发病率和死亡率；在缺乏标准和有效的筛查方式的情况下，诊所经常求助于肛门镜检查，一种类似于阴道镜检查的诊断程序，并对所有艾滋病毒阳性的男男性行为者进行定向活检。在北加州Kaiser Permanente，我们招募了1000名hiv阳性的男男性接触者，进行了一项为期2年的研究，以描述HPV的自然史，并评估各种检测流行、1年累积和2年累积肛门癌前病变和癌症的临床应用。