Studies of Rare Cancers

罕见癌症的研究

• 批准号: 8349573
• 负责人: LOUISE BRINTON
• 金额: $ 128万
• 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/8349573
• 关键词: Affect; Africa South of the Sahara; African American; Antibodies; Antibody Specificity; Anus; Area; Asia; Biopsy; CYP2E1 gene; California; Cancer Etiology; Case-Control Studies; Caucasians; Caucasoid Race; Childhood; China; Chinese People; Cholangiocarcinoma; Cholelithiasis; Chromosomes, Human, Pair 14; Cirrhosis; Clinic; Clinical; Cohort Studies; Colposcopy; Consumption; DNA Repair; DNA Repair Gene; Data; Data Linkages; Databases; Developing Countries; Development; Diabetes Mellitus; Diagnostic Procedure; Disease; Dust; Enrollment; Enzymes; Epididymitis; Etiology; Europe; Evaluation; Exogenous Factors; Exposure to; Family; Family Study; Family history of; Female; Formaldehyde; Fracture; Fumonisin B1; Gene Expression; General Population; Genes; Genetic Markers; Gynecomastia; HBV and Aflatoxin; HIV; Hepatitis B Virus; Hepatitis C virus; Histologic; Hormones; Hospitalization; Human Herpesvirus 4; Human Papillomavirus; Immune; Incidence; Individual; Infection; Intake; International; Intrahepatic Cholangiocarcinoma; Investigation; Klinefelter' s Syndrome; Life; Link; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Malignant neoplasm of liver; Malignant neoplasm of male breast; Malignant neoplasm of nasopharynx; Medical; Metabolic syndrome; Methods; Modality; Molecular Profiling; Morbidity - disease rate; Nasopharyngeal Neoplasms; Natural History; Nitrites; Nitrosamine Metabolism; Nitrosamines; Normal Cell; Obesity; Occupational Exposure; Orchitis; Other Genetics; Pathogenesis; Pattern; Persons; Population; Primary carcinoma of the liver cells; Recording of previous events; Relative (related person); Research; Resort; Ribes; Risk; Risk Factors; Screening procedure; Serologic tests; Taiwan; Testing; Tissue Sample; Tissues; United States Department of Veterans Affairs; United States National Institutes of Health; Variant; Weaning; Woman; Wood material; base; cancer risk; care systems; case control; cigarette smoking; cohort; computerized; follow-up; insight; interest; malignant breast neoplasm; men who have sex with men; mortality; neoplastic cell; organochlorine pesticide; tumor

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 cancer development, other genetic and exogenous factors are also thought to be important. To investigate 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 NPC multiplex families have been shown in our study to have elevated levels of antibodies against EBV compared to the general population. To follow-up on this finding, we have evaluated the value of EBV serology to predict subsequent NPC risk among unaffected individuals from NPC multiplex families. We observed that individual with elevated antibody levels against several EBV markers are at a 4 to 6-fold increased risk of developing NPC within 10 years, but the low specificity of the antibodies evaluated suggest that improvements are required before such serology-based tests can be used clinically. 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 are including 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. We are also hoping to obtain breast cancer tissue samples from some of the studies. 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 have enrolled about 400 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.ribe 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. cer 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 are including 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. We are also hoping to obtain breast cancer tissue samples from some of the studies. 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 have enrolled about 400 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.ribe 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. ulative, and 2-year cumulative anal precancer and cancer.ribe 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.

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，未受影响的NPC多重家族个体的EBV抗体水平升高。为了进一步研究这一发现，我们评估了EBV血清学在预测鼻咽癌多重家族中未受影响个体后续鼻咽癌风险方面的价值。我们观察到，针对几种EBV标记物的抗体水平升高的个体在10年内发生NPC的风险增加了4至6倍，但所评估的抗体的低特异性表明，在这种基于血清学的测试可用于临床之前，需要改进。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，是世界上第六大最常见的癌症，也是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。我们最近扩大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，其中包括来自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。我们也希望从一些研究中获得乳腺癌组织样本。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，我们在一项为期2年的研究中招募了大约400名hiv阳性的男男性行为者，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效用。了解HPV的自然历史，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。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，其中包括来自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。我们也希望从一些研究中获得乳腺癌组织样本。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，我们在一项为期2年的研究中招募了大约400名hiv阳性的男男性行为者，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效用。了解HPV的自然历史，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。累积性和2年累积性肛门癌前病变和癌症。了解HPV的自然历史，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。