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）具有非常不同的地理和种族分布，在中国东南部的中国族中以高率发生，而白种人人口的速度要低得多。虽然据信爱泼斯坦巴尔病毒（EBV）的感染对于癌症的发展是必要的，但其他遗传和外源性因素也被认为很重要。为了研究与NPC病因相关的因素，台湾进行了两项研究 - 对约1,000名个体的病例对照研究和大约3,000名个人（350个家庭）的多重家庭研究。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，我们的研究中已经证明了来自NPC多重家族的未经无效的个体对EBV的抗体水平升高。为了跟进这一发现，我们评估了EBV血清学的价值，以预测NPC多重多重家族未受影响的个体中随后的NPC风险。我们观察到，针对几种EBV标记的抗体水平升高的个体在10年内增加了NPC发展的风险4至6倍，但是评估的抗体的低特异性表明，在临床上使用此类基于血清的测试之前，需要进行改进。原发性肝癌，由两种主要的组织学类型组成，分别是肝细胞癌（HCC）和肝内胆管癌（ICC），是世界上第六次最常见的癌症，也是癌症死亡率的第三个常见原因。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类型肝癌风险的关系。最近，我们扩大了对乳腺癌病因的兴趣，还包括很少发生的男性乳腺癌。在大型NIH-AARP队列研究中的分析中，我们确定了女性亲戚，肥胖，身体不活动的乳腺癌家族史以及与风险增加有关的骨骼骨折病史。美国退伍军人事务的一项调查计算机化医疗系统数据库发现，与Klinefelter综合征，肥胖，糖尿病，妇科症，卵形炎/附生炎和杂子症相关的男性乳腺癌的风险增加了（后者仅在非裔美国人中）。我们目前正在汇总分析中跟踪这些发现，其中包括大多数病例对照和队列调查的数据。队列研究将在评估与遗传标记和内源激素的关系方面特别有价值。我们还希望从一些研究中获得乳腺癌组织样品。与男性发生性关系（MSM）的人类免疫缺陷病毒（HIV）阳性男性有肛门癌的风险，遇到居住在发展中国家的未经检查的妇女的宫颈癌风险。目前尚无对肛门癌症筛查HIV阳性MSM筛查的可接受的方法来降低由于肛门癌的发病率和死亡率。在没有标准且有效的筛查方式的情况下，诊所经常诉诸于阴道镜的诊断程序，类似于阴道镜检查以及所有HIV阳性MSM的定向活检。在Kaiser Permanente北加州，我们在一项为期两年的研究中招募了约400个HIV阳性MSM，以描述HPV的自然历史，并评估各种测试的临床实用性，以检测普遍的，一年的累积和2年累积的肛门肛门和癌症。累积的肛门预科剂和癌症。 CER还包括关注很少发生的雄性乳腺癌。在大型NIH-AARP队列研究中的分析中，我们确定了女性亲戚，肥胖，身体不活动的乳腺癌家族史以及与风险增加有关的骨骼骨折病史。美国退伍军人事务的一项调查计算机化医疗系统数据库发现，与Klinefelter综合征，肥胖，糖尿病，妇科症，卵形炎/附生炎和杂子症相关的男性乳腺癌的风险增加了（后者仅在非裔美国人中）。我们目前正在汇总分析中跟踪这些发现，其中包括大多数病例对照和队列调查的数据。队列研究将在评估与遗传标记和内源激素的关系方面特别有价值。我们还希望从一些研究中获得乳腺癌组织样品。与男性发生性关系（MSM）的人类免疫缺陷病毒（HIV）阳性男性有肛门癌的风险，遇到居住在发展中国家的未经检查的妇女的宫颈癌风险。目前尚无对肛门癌症筛查HIV阳性MSM筛查的可接受的方法来降低由于肛门癌的发病率和死亡率。在没有标准且有效的筛查方式的情况下，诊所经常诉诸于阴道镜的诊断程序，类似于阴道镜检查以及所有HIV阳性MSM的定向活检。在Kaiser Permanente北加州，我们在一项为期两年的研究中招募了约400个HIV阳性MSM，以描述HPV的自然历史，并评估各种测试的临床实用性，以检测普遍的，一年的累积和2年累积的肛门肛门和癌症。累积的肛门预科剂和癌症。 Ulative和2年累积肛门预科剂和癌症。RibeHPV的自然历史，并评估了各种测试的临床实用性，以检测普遍存在，1年累积和2年累积的肛门预科剂和癌症。