Genetic Epidemiology
遗传流行病学
基本信息
- 批准号:8349551
- 负责人:
- 金额:$ 110.46万
- 依托单位:
- 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:
- 关键词:21 year oldAdultAffectAgeAnatomic SitesAreaAutoimmune DiseasesAutoimmunityB-Cell NonHodgkins LymphomaBRAF geneBedsBloodBrainBrain NeoplasmsBreastBreast Cancer Risk FactorCanadaCandidate Disease GeneCase-Control StudiesCategoriesCellsCharacteristicsChildhood MedulloblastomasChordomaChronicClinicClinicalComputer softwareCore FacilityCutaneous MelanomaDNADataDefectDevelopmentDiagnosisDivision of Cancer Epidemiology and GeneticsDuct (organ) structureDysmyelopoietic SyndromesDysplastic NevusERBB2 geneEmbryoEpidemiologic StudiesEpidermal Growth Factor ReceptorEpithelial CellsEstrogensEtiologyEuropeanEvaluationFactor AnalysisFamilyFamily history ofFreezingGene ExpressionGeneral PopulationGenesGeneticGenetic ResearchGliomaGoalsHematologic NeoplasmsHereditary DiseaseHeterogeneityHigh-Risk CancerHistocompatibility TestingHodgkin DiseaseHormonalHormone ReceptorHormonesHospitalizationImage AnalysisImmuneImmune systemIndividualInfectionInflammationInflammatoryInterviewInvestigationItalyLesionLinkLobularLymphoidLymphomaMalignant Bone NeoplasmMalignant NeoplasmsMalignant lymphoid neoplasmMeasurementMeasuresMediatingMedicalMelanocytic nevusMetabolismMethylationMolecularMonoclonal gammopathy of uncertain significanceMorphologyMultiple MyelomaMutationMyeloproliferative diseaseNeoplasm MetastasisNeoplasmsNervous System PartNevi and MelanomasNevusNot Hispanic or LatinoOncogenesOutcomePathologistPathway interactionsPatientsPatternPhiladelphiaPigmentation physiologic functionPolandPolishesPopulationProcessQuestionnairesReceptor GeneRecordsRegistriesRegulationRelative (related person)Renal carcinomaReproductive HistoryRestRiskRisk FactorsSan FranciscoScandinaviaSecond Primary CancersSiteSkeletonSkinSkin tanningSlideSolid NeoplasmSomatic MutationSpainSpecimenStaining methodStainsStem cellsSun ExposureSunscreening AgentsSurrogate MarkersSusceptibility GeneTestingThe SunTimeTissue MicroarrayTissue SampleTissuesTumor SubtypeTumor TissueUnited StatesUniversitiesVariantWomanalpha-Melanocyte stimulating hormonebasecancer geneticscancer typecandidate markercarcinogenesiscase controlcdc Genesdata registrydisorder riskgenetic epidemiologyhigh riskhormone biosynthesishuman ESR1 proteininfancyleukemiamalignant breast neoplasmmelanomamolecular markerpopulation basedreceptortelomeretissue fixingtumor
项目摘要
Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Further analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest, non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds, and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy, showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene, in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected to extend the analyses of association between melanoma risk and pigmentation and immune-related genes; evaluation of these additional populations is in process. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure, body site, nevi count, susceptibility genes and other factors is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. Analysis of genes involved in telomere regulation in relation to nevi count and progression to melanoma is also ongoing. Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. An expanded project has been developed to collect personal and family medical history, buccal cells and slides of tumor tissue from sporadic chordoma patients from throughout the United States and Canada. The project will collect up to 400 patients diagnosed with chordoma at any age and anatomic site. We collaborated with Yale University Tissue Microarray (TMA) core facility and successfully built TMAs of invasive tumors collected from the Polish Breast Cancer Study. Analyses of immunohistochemically (IHC) stained tumors (N=842) for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways suggested that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We also stained all TMAs for six markers (ER-alpha, ER-beta, PR, HER2, EGFR, and CK5) using Automated Quantitative Analysis (AQUA) and showed that AQUA analyses of tumors represented in TMAs provide reliable, quantitative measures of marker expression. We have also compared some commercially available imaging analysis software to pathologists measurements and our data suggested that automated analysis of IHC markers represents a promising approach for analyzing large numbers of breast cancer tissues in epidemiologic investigations. We have expanded our analyses of risk factor heterogeneity by tumor subtypes to a pooled analysis of 35,568 breast cancer cases from 34 studies participating in the Breast Cancer Association Consortium (BCAC) and we found that reproductive factors and BMI are most clearly related to hormone receptor positive tumors. In addition to the analysis of invasive tumors, we are also measuring and analyzing marker expression in normal breast epithelial cells (terminal duct lobular units, TDLUs) in 150 Polish breast cancer cases and correlating marker data with risk factors, clinical characteristics and morphology (TDLU involution). In addition to TMA analyses of candidate markers in fixed tissues, we have conducted tumor profiling for gene expression, CpG methylation, and copy number changes in frozen tumors from a subset of Polish breast cancer cases to better define molecular subtypes that are associated with distinct etiologic pathways. We are continuing to conduct studies using the Swedish linked registry data to define hematologic malignancies that co-aggregate in families, to detect immune-related and inflammatory conditions (based on hospitalization records) that pre-dispose to these malignancies and to define characteristics that affect progression of these conditions. We found that relatives of AML or MDS patients were not at increased risk for AML although there was a modest and borderline significant increased risk for all hematologic malignancies combined and for all solid tumors combined. Relatives of AML patients who were diagnosed under the age of 21 were at significantly increased risk for AML and MDS suggesting heterogeneity of AML etiology. Analyses of MGUS (precursor to myeloma and other lymphoid maligncancies) patients are continuing. As with other hematologic malignancies studied previously, infections, inflammation, and autoimmunity are all associated with increased risk for subsequent MGUS. Patients with myeloma are at increased risk for second cancers including AML and MDS. We are currently analyzing factors that affect progression of MGUS to myeloma and other lymphoid malignancies. isposition to autoimmune diseases and lymphoma. We have found that hospitalization for infection in infancy is associated with later development of aggressive B-cell NHLs but not Hodgkin lymphoma. Thus, infection in infancy could be a surrogate marker of immune system defects. We have found that autoimmune diseases and infections are also associated with myeloid malignancies. For example, AML and MDS patients show a significant association with several autoimmune diseases and infections that are evident as much as 5 years before the onset of leukemia/myelodysplasia, respectively.
这个遗传流行病学项目的许多调查都来自于对癌症高风险家庭的观察或其他病因学研究。对来自费城和旧金山黑色素瘤诊所的718名非西班牙裔白人皮肤黑色素瘤患者的病例对照研究的进一步分析显示,在大部分时间使用防晒霜的易感人群中,黑色素瘤的风险略有下降,但不显著。年轻女性是最可能使用日光浴床的人群,而日光浴床的使用与患黑色素瘤的风险有关。那些使用美黑床的人更有可能在不经常暴露在阳光下的部位长黑色素瘤。这些观察结果可能有助于解释普通人群中年轻女性黑色素瘤发病率上升和分布变化的原因。在意大利东北部进行的183例黑色素瘤病例和179例对照病例的问卷调查数据、肿瘤和DNA研究显示,黑色素皮质素-1受体(MC1R)基因的种系变异与BRAF癌基因体细胞突变的黑色素瘤之间存在很强的相关性,这些患者的黑色素瘤发生在身体暴露在阳光下的区域,并且患有有限的慢性太阳损伤。我们在一个独立的人群中证实了这种关联。已经收集了来自其他地中海人群的数据,以扩展黑色素瘤风险与色素沉着和免疫相关基因之间关系的分析;对这些新增人口的评价正在进行中。已收集黑色素瘤组织标本,计划分析黑色素瘤病变与日晒、体位、痣数、易感基因等因素的关系。导致黑色素瘤发展的潜在途径之一包括失去对普通黑色素细胞痣的调节,这些黑色素细胞痣获得非典型或发育不良的特征,可以进一步发展为肿瘤。为了研究这一途径,我们目前正在意大利和西班牙收集来自同一受试者的正常皮肤、普通黑素细胞痣、发育不良痣、黑色素瘤和黑色素瘤转移瘤的多个组织样本。我们计划研究细胞周期中多个基因突变的表达和存在,以及一系列组织样本和种系DNA的转导途径,以探索黑色素瘤通过痣发展的机制。与痣计数和黑色素瘤进展相关的端粒调控基因的分析也在进行中。对来自DCEG成人脑肿瘤病例对照研究的365例胶质瘤患者的亲属进行了个人/家族病史和其他危险因素的访谈。脊索瘤是一种罕见的原发性恶性骨肿瘤,主要发生在胚胎脊索干细胞未能正常退化的轴骨中。已经开展了一个扩大的项目,收集来自美国和加拿大各地散发性脊索瘤患者的个人和家族病史、颊细胞和肿瘤组织切片。该项目将收集多达400名在任何年龄和解剖部位被诊断患有脊索瘤的患者。我们与耶鲁大学组织微阵列(TMA)核心设备合作,成功构建了波兰乳腺癌研究中收集的浸润性肿瘤的TMA。免疫组织化学(IHC)染色肿瘤(N=842)对18个参与激素生物合成、代谢和受体介导途径的分子标志物进行分析,表明乳腺癌的危险因素可能因分子亚型和以激素标志物共表达为特征的激素途径而异。我们还使用自动定量分析(AQUA)对所有tma进行了6种标记物(er - α、er - β、PR、HER2、EGFR和CK5)的染色,结果表明,对tma中代表的肿瘤进行AQUA分析提供了可靠的、定量的标记物表达测量。我们还将一些市售的成像分析软件与病理学家的测量结果进行了比较,我们的数据表明,IHC标记物的自动分析代表了一种在流行病学调查中分析大量乳腺癌组织的有前途的方法。我们扩大了对肿瘤亚型风险因素异质性的分析,对参与乳腺癌协会联盟(BCAC)的34项研究中的35,568例乳腺癌病例进行了汇总分析,我们发现生殖因素和BMI与激素受体阳性肿瘤的关系最为明显。除了分析浸润性肿瘤外,我们还测量和分析了150例波兰乳腺癌病例中正常乳腺上皮细胞(终末导管小叶单位,TDLUs)中的标志物表达,并将标志物数据与危险因素、临床特征和形态学(TDLU退化)相关联。除了对固定组织中的候选标记物进行TMA分析外,我们还对来自波兰乳腺癌病例子集的冷冻肿瘤进行了基因表达、CpG甲基化和拷贝数变化的肿瘤谱分析,以更好地定义与不同病因途径相关的分子亚型。我们正在继续使用瑞典相关登记数据进行研究,以确定在家庭中共同聚集的血液恶性肿瘤,检测易患这些恶性肿瘤的免疫相关和炎症性疾病(基于住院记录),并确定影响这些疾病进展的特征。我们发现AML或MDS患者的亲属患AML的风险没有增加,尽管所有血液恶性肿瘤合并和所有实体肿瘤合并的风险都有适度和临界显著的增加。年龄在21岁以下的AML患者亲属患AML和MDS的风险显著增加,提示AML病因存在异质性。对MGUS(骨髓瘤和其他淋巴细胞恶性肿瘤的前体)患者的分析仍在继续。与先前研究的其他血液系统恶性肿瘤一样,感染、炎症和自身免疫都与随后发生MGUS的风险增加有关。骨髓瘤患者患急性髓性白血病和MDS等第二种癌症的风险增加。我们目前正在分析影响MGUS向骨髓瘤和其他淋巴细胞恶性肿瘤发展的因素。易患自身免疫性疾病和淋巴瘤我们发现,在婴儿期因感染住院治疗与侵袭性b细胞nhl的后期发展有关,但与霍奇金淋巴瘤无关。因此,婴儿期感染可能是免疫系统缺陷的替代标志。我们发现自身免疫性疾病和感染也与髓系恶性肿瘤有关。例如,AML和MDS患者与几种自身免疫性疾病和感染有显著的相关性,这些疾病和感染分别在白血病/骨髓增生异常发生前5年就明显存在。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ALISA GOLDSTEIN其他文献
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