Genetic Investigation of NPC and HCC in a Chinese Population

中国人群鼻咽癌和肝癌的基因研究

• 批准号: 7733235
• 负责人: Cheryl Winkler
• 金额: $ 12.33万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/7733235
• 关键词: Aflatoxin B1; Aflatoxins; Africa; African; Alcohols; Alleles; Animal Feed; Animals; Antibodies; Area; Asia; Biological Markers; CYP2E1 gene; Cancer Etiology; Candidate Disease Gene; Capsid; Carcinogens; Carcinoma; Case-Control Studies; Cause of Death; Cessation of life; Chemicals; China; Chinese People; Chronic; Chronic Active Hepatitis; Cirrhosis; Clinical; Code; Consumption; Country; DNA; Data; Data Collection; Databases; Detection; Developed Countries; Developing Countries; Development; Diet; Dietary Factors; Disease; Enrollment; Environmental Carcinogens; Environmental Exposure; Environmental Risk Factor; Epstein-Barr Virus Infections; Exposure to; Family; Family history of; Far East; Female; Fire - disasters; Fishes; Food; Food Preservatives; GSTM1 gene; GSTP1 gene; GSTT1 gene; GSTT1 protein; Gene Targeting; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; HIV Infections; Haplotypes; Hepatitis B Virus; Hepatocarcinogenesis; Herb; High Prevalence; Human; Human Herpesvirus 4; Immunoglobulin A; In Vitro; Incidence; Individual; Infection; Investigation; Knock-out; Laboratories; Leukocytes; Liver; Malignant Neoplasms; Meat; Metabolic; Metabolic Biotransformation; Methods; Modeling; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Nasopharynx Carcinoma; Nitrates; Nitrosamines; Occupational; Occupational Exposure; Other Genetics; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Peripheral; Persons; Phase; Phase I Clinical Trials; Phorbol Esters; Plants; Plasma; Population; Predisposition; Prevalence; Primary carcinoma of the liver cells; Province; Quality Control; Questionnaires; RNA Splicing; Rate; Records; Relative Risks; Reporting; Research; Risk; Risk Factors; Role; Sampling; Simian B disease; Single Nucleotide Polymorphism; Site; Smoking; Solvents; Source; Southeastern Asia; Study Subject; TP53 gene; Testing; Therapeutic; Tissues; Tobacco smoking; Triad Acrylic Resin; United States; Variant; Viral; Virus; Virus Replication; Water; Woman; Wood material; base; cancer risk; carcinogenesis; case control; design; dosage; gene discovery; gene environment interaction; gene interaction; genetic analysis; glutathione S-transferase M1; glutathione S-transferase pi; improved; male; men; nitrate; repaired; sample collection; tobacco exposure; urinary

The NPC collaborative study has as its primary objective the discovery of genes and characterization of variant alleles associated with the development of NPC in a Chinese population. NPC is a leading cause of cancer deaths in the Cantonese population in China. Case-control studies have indicated a strong role for environmental factors, including food preservatives (carcinogenic nitrosamines), salt-preserved fish, and phorbol esters in herbs and plants that are commonly consumed among ethnic populations with the highest NPC rates. Familial aggregation of NPC and evidence of linkage have been observed in China and in other countries. Since chronic EBV replication, as evidenced by detection of immunoglobulin A (IgA) antibody against EBV viral capsid, and exposure to dietary factors are predictive of NPC but do not explain all of the disease, we have hypothesized that there may also be genetic factors contributing to the development of NPC. We have therefore developed a case-control study to investigate the genetic correlates of NPC in a highly impacted region of southern China. HCC is one of the most common cancers worldwide and a leading cause of death in many countries, especially in East Asia and sub-Saharan African. HCC is also increasing in developed countries. In the United States the incidence of HCC increased from 1.4 per 100,000 population for the period from 1976 to 1980 to 2.4 per 100,000 for the period from 1991 to 1995. Both aflatoxin B1 (AFB1) contamination and HBV infection are well-recognized risk factors for HCC. AFB1 is one of the most potent carcinogens to which humans are exposed. AFB1 has a wide distribution and high concentration in human and animal foods particularly in HCC endemic regions along the southeast seacoast. Among them Guangxi is a HCC high-risk region where both AFB1 contamination and HBV infection are common. In Southeast Asia and certain regions of Africa, aflatoxin consumption and infection by HBV are important factors giving rise to the extraordinarily high incidence rates (24.235.5/100 000) of HCC in these areas. HBV-induced chronic active hepatitis and cirrhosis constitute major factors in liver carcinogenesis. HBV is associated with 70-75% of all HCC cases in Asia, the continent with the highest prevalence of HBV. A synergistic effect of AFB1 and HBV in increasing risk for HCC has been reported in many studies. We hypothesize that if there is a host genetic effect on oxidative stress leading to the development of HCC, it would be most evident in a population exposed to environmental hepatocarcinogens where exposure and dosage is strong enough to manifest the genetic effects. Both animal and in vitro studies indicate that oxidative stress might contribute to the key pathways in either virus or chemical induced hepatocarcinogenesis. There is evidence for strong correlations between environmental carcinogens and oxidative stress in study participants with both HBV infection and exposures to environmental carcinogens, providing an opportunity to screen candidate genotypes/haplotypes for HCC risk in this unique population. We will be using a candidate gene approach selecting genes involved in oxidative repair pathways. For targeted genes, all SNPs within regulatory, splice sites or coding regions (both synonymous and nonsynonymous) will be selected and htSNPs added to capture more than 95% of the variation. Gene-gene and gene-environment interactions will be fully analyzed in this model. The findings will be further compared with a HBV outcome case-control study of subjects from northern China. Accomplishments: Completion of enrollment and data collection for the NPC study: Enrollment, data collection, and DNA extractions for the NPC study Phase I and Phase II of the NPC study have been completed. Family triads were enrolled for haplotype inference and for quality control assessment of the pilot. No Mendelian errors were observed within any of the family triads attesting to the fidelity of sample handling and genotyping. Phase II is a cross-sectional case-control study and included a questionnaire to capture environmental factors, including occupational, dietary and tobacco exposures. The completion of enrollment of Phase I and II participants (n=4000) and the addition of environmental exposure data provides adequate power to discover main effect genes and to test gene-environment interactions. To investigate the roles of genetic variations of carcinogen metabolic genes in NPC susceptibility in Han Chinese population, polymorphisms CYP2E1, GSTP1, MPO, NQO1 and deletion alleles that knockout GSTM1 and GSTT1 expression were genotyped in NPC cases and controls. We found male individuals who carried GSTM1/GSTT1 double null genotype had a higher risk for NPC (OR = 1.76, 95% CI = 1.04-2.97, p = 0.03); this association was not observed for females. We are now looking for interactions with smoking since more than 75% of men report tobacco smoking but less than 10% of women. Our results suggest that the GSTM1/GSTT1 double null genotype may be a risk factor for NPC in southern China, but this result requires replication. We have also completed analysis of environmental risk factors. Domestic exposures to wood fires, occupational exposures to solvents, and a family history of NPC were all significantly associated with increased risk for the development of NPC. Sample collection and biomarker status for the HCC study: DNA from HCC liver tissues from HBV-infected persons and peripheral leukocytes of HBV-infected controls, together with plasma and urinary biomarkers of HIV infection, aflatoxin exposure and oxidative stress have been completed. Candidate genes and SNPs have been selected for genotyping using the Illumina Goldengate platform. These include genes involved in carcinogenesis, biotransformation and oxidative damage repair pathways. SNPs were selected based on their putative or known function or because they were haplotype tagging All samples are from HCC patients and local controls from Guangxi Province, a HCC endemic area in China where both AFB1 contamination and HBV infection are well-recognized risk factors. A database of all laboratory and clinical records, including carcinogen (aflatoxin) and oxidative stress biomarkers, has been established. We have also completed sequencing of p53 in patients with HCC and domestic exposures to aflatoxin and alcohol.

NPC合作研究是其主要目标，即在中国人群中与NPC发展相关的变异等位基因的发现和表征。 NPC是中国广东话人口癌症死亡的主要原因。 病例对照研究表明，在NPC率最高的种族中通常消耗的草药和植物中，包括粮食防腐剂（饮食中的硝基胺），保存盐的鱼类和植物中的凤凰酯在内的环境因素中起着重要作用。 在中国和其他国家，已经观察到了NPC的家族汇总和联系的证据。由于慢性EBV复制，因此检测到针对EBV病毒capsid的免疫球蛋白A（IGA）抗体证明，暴露于饮食因素是NPC的预测，但并不能解释所有疾病，我们假设可能有遗传因素有助于NPC的发展。因此，我们已经开发了一项病例对照研究，以研究中国南部高度影响地区NPC的遗传相关性。 HCC是全球最常见的癌症之一，也是许多国家，尤其是在东亚和撒哈拉以南非洲的主要死亡原因。发达国家的HCC也在增加。在美国，HCC的发病率从1976年的每100,000人口1.4人口增加到1991年至1995年的每100,000人。黄曲霉毒素B1（AFB1）污染和HBV感染都是HCC的良好识别危险因素。 AFB1是人类暴露的最有效的致癌物之一。 AFB1在人类和动物食品中具有广泛的分布和高浓度，尤其是在东南海岸沿海地区的地方性地区。其中，广西是HCC高风险区域，在该区域中，AFB1污染和HBV感染均为常见。在东南亚和非洲的某些地区，HBV的黄曲霉毒素消耗和感染是这些领域中HCC的发病率极高（24.235.5/100 000）的重要因素。 HBV诱导的慢性活性肝炎和肝硬化是肝癌发生的主要因素。 HBV与亚洲所有HCC病例的70-75％有关，该大陆的患病率最高。在许多研究中，已经报道了AFB1和HBV对增加HCC风险增加的协同作用。我们假设，如果宿主遗传对氧化应激产生导致HCC发展的影响，那么在暴露于环境肝癌的种群中，最明显的是，暴露和剂量足以表现出遗传作用。动物和体外研究都表明，氧化应激可能有助于病毒或化学诱导的肝癌发生的关键途径。有证据表明，在HBV感染和对环境致癌物暴露的研究参与者中，环境致癌物与氧化应激之间存在很强的相关性，这为在这个独特人群中提供了筛查候选基因型/单倍型的机会。我们将使用候选基因方法选择涉及氧化修复途径的基因。对于有针对性的基因，将选择调节性基因，剪接位点或编码区域（同义词和非同义词），并添加HTSNP，以捕获超过95％的变化。基因基因和基因环境相互作用将在该模型中进行全面分析。与来自中国北部的受试者的HBV结果案例对照研究将进一步比较。成就：NPC研究的入学率和数据收集：NPC研究I阶段I和NPC研究II期的注册，数据收集和DNA提取已完成。家庭三合会被招募进行单倍型推断和试点的质量控制评估。在任何家庭三合会中都没有观察到孟德尔的错误，证明了样品处理和基因分型的保真度。 II期是一项横断面病例对照研究，其中包括一份问卷，以捕获包括职业，饮食和烟草暴露在内的环境因素。 I和II期参与者的入学人数（n = 4000）的完成，并增加环境暴露数据提供了足够的能力来发现主要效应基因并测试基因 - 环境相互作用。为了研究致癌代谢基因在NPC易感性中的遗传变异，在NPC案例和对照组中基于NPC病例和对照组的基因分类。我们发现携带GSTM1/GSTT1双重NULL基因型的男性患者的NPC风险较高（OR = 1.76，95％CI = 1.04-2.97，p = 0.03）;女性未观察到这种关联。我们现在正在寻找吸烟的互动，因为超过75％的男性报告吸烟，但不到10％的女性吸烟。我们的结果表明，GSTM1/GSTT1双重零基因型可能是中国南部NPC的危险因素，但该结果需要复制。我们还完成了对环境风险因素的分析。 国内暴露于木火灾，对溶剂的职业接触以及NPC的家族史都与NPC发展的风险增加显着相关。 HCC研究的样品收集和生物标志物状态：来自HBV感染者的HCC肝组织的DNA和HBV感染对照的外周白细胞，以及HIV HIV感染的血浆和尿生物标志物，AFLATOXIN暴露和氧化应激的血浆和尿生物标志物。已选择使用Illumina Goldengate平台选择候选基因和SNP进行基因分型。这些包括涉及癌变，生物转化和氧化损伤修复途径的基因。根据其推定或已知功能选择SNP，或者因为它们是单倍型标记的所有样本都是来自HCC患者的HCC患者和来自广西省的局部对照。已经建立了所有实验室和临床记录的数据库，包括致癌物（黄曲霉毒素）和氧化应激生物标志物。我们还完成了HCC患者以及对黄曲霉毒素和酒精的家庭暴露的患者的p53测序。