Genetic Epidemiology

遗传流行病学

• 批准号: 8565412
• 负责人: ALISA GOLDSTEIN
• 金额: $ 93.47万
• 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/8565412
• 关键词: Adult; Affect; Age; Anatomic Sites; Area; Autoimmune Diseases; BRAF gene; Bacterial Infections; Beds; Biological Markers; Blood; Brain; Brain Neoplasms; Breast; Breast Cancer Risk Factor; Canada; Candidate Disease Gene; Case-Control Studies; Categories; Cells; Characteristics; Childhood Medulloblastomas; Chordoma; Chronic; Clinic; Clinical; Collaborations; Comprehensive Cancer Center; Computer software; Core Facility; Cutaneous Melanoma; DNA; Data; Development; Diagnosis; Disease; Division of Cancer Epidemiology and Genetics; Duct (organ) structure; Dysplastic Nevus; ERBB2 gene; Embryo; Enrollment; Epidemiologic Studies; Epidermal Growth Factor Receptor; Estrogens; Etiology; European; Family; Family history of; Feasibility Studies; First Degree Relative; Freezing; Gene Expression; General Population; Genes; Genetic; Genetic Research; Glioma; Goals; Hematologic Neoplasms; Hereditary Disease; Heterogeneity; High-Risk Cancer; Histocompatibility Testing; Hormonal; Hormone Receptor; Hormones; Hospitalization; Image Analysis; Immune; Individual; Infection; Inflammatory; Interview; Investigation; Italy; Lesion; Link; Lobular; Malignant Bone Neoplasm; Malignant Neoplasms; Malignant lymphoid neoplasm; Measurement; Measures; Mediating; Medical; Medical center; Melanocytic nevus; Metabolism; Methylation; Molecular; Monoclonal gammopathy of uncertain significance; Morphology; Multiple Myeloma; Mutation; Myeloproliferative disease; Neoplasm Metastasis; Neoplasms; Nervous System Part; Nevi and Melanomas; Nevus; Not Hispanic or Latino; Oncogenes; Outcome; Pathologist; Pathway interactions; Patients; Pattern; Phenotype; Philadelphia; Pigmentation physiologic function; Pilot Projects; Poland; Polishes; Population; Predisposition; Questionnaires; Receptor Gene; Records; Registries; Regulation; Relative (related person); Renal carcinoma; Reproductive History; Rest; Risk; Risk Factors; Role; Sampling; San Francisco; Scandinavia; Site; Skeleton; Skin; Skin tanning; Slide; Solid Neoplasm; Somatic Mutation; Spain; Specimen; Staining method; Stains; Stem cells; Structure; Sun Exposure; Sunscreening Agents; Susceptibility Gene; Testing; The Sun; Time; Tissue Microarray; Tissue Sample; Tissues; Tumor Subtype; Tumor Tissue; United States; Universities; University Hospitals; Variant; Virus Diseases; Waldenstrom Macroglobulinemia; alpha-Melanocyte stimulating hormone; base; cancer genetics; cancer type; candidate marker; carcinogenesis; case control; cdc Genes; data registry; disorder risk; follow-up; genetic epidemiology; high risk; hormone biosynthesis; human ESR1 protein; malignant breast neoplasm; melanoma; molecular marker; multiple myeloma M Protein; population based; receptor; telomere; tissue fixing; tumor; young woman

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 and harmonized to extend the analyses of association between melanoma risk and several risk factors, also including immune-related genes. In this combined sample, we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. 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. In addition, we are developing a new melanoma tissue-based study to identify clinically and etiologically relevant subtypes of melanoma. We plan to prospectively identify and enroll 1,500 primary melanoma patients diagnosed at University Hospitals Case Medical Center (UHCMC)/Case Comprehensive Cancer Center (Case CCC). We will classify melanomas into molecular subtypes using an integrated tumor profiling approach and will associate each molecular subtype with known melanoma risk factors (including both genetic and environmental), host pigmentation characteristics, and clinical characteristics and outcomes. Currently, we are conducting a pilot study to test the technical feasibility of this study. 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. Analysesof 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 evaluating the morphology and molecular characteristics of terminal duct lobular units (TDLUs), the structures from which breast cancers arise, in breast cancer cases. We found that TDLU involution was significantly less pronounced in breasts containing core basal phenotype (CBP) tumors as compared to luminal tumors. We are developing collaborations to confirm and extend these findings using materials from other studies. We are also measuring and analyzing marker expression in normal TDLUs in 150 Polish breast cancer cases and correlating marker data with risk factors and clinical characteristics. 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 previously described increased risk of lymphoid malignancies among first-degree relatives of patients with Waldenstrom macroglobulinemia (WM) or Lymphoplasmacytic lymphoma. We recently demonstrated that relatives were not at increased risk for myeloid malignancies or for solid tumors. We found that patients with MGUS are at increased risk (2-fold, p 0.05) for subsequent infections (at 5 and 10 year follow-up). Both bacterial and viral infections were involved. Those with higher M-protein concentrations were at greatest risk. However, development of infections did not predict subsequent risk of and MGUS patient developing myeloma, WM, or related malignancy. In another study, prior infections, inflammatory diseases, and autoimmune diseases were associated with an increased risk of MGUS. A family history of autoimmune disease was also associated with subsequent MGUS suggesting some shared susceptibility. We are currently analyzing biological markers that affect progression of MGUS to myeloma and other lymphoid malignancies.

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。来自其他地中海人群的数据已被收集和协调，以扩大对黑色素瘤风险与若干风险因素（包括免疫相关基因）之间关系的分析。在这个联合样本中，我们确定了端粒相关基因在黑色素瘤病因学中的作用的暗示证据。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。此外，我们正在开展一项新的基于黑色素瘤组织的研究，以确定临床和病因学相关的黑色素瘤亚型。我们计划前瞻性地识别并招募1500名在大学医院病例医学中心(UHCMC)/病例综合癌症中心（CCC）诊断的原发性黑色素瘤患者。我们将使用综合肿瘤分析方法将黑色素瘤分为分子亚型，并将每种分子亚型与已知的黑色素瘤危险因素（包括遗传和环境因素）、宿主色素沉着特征、临床特征和结果联系起来。目前，我们正在进行一项先导研究，以测试这项研究在技术上的可行性。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）的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的分析表明，乳腺癌的危险因素可能因分子亚型和激素标志物共同表达的激素途径而异。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。除了对浸润性肿瘤的分析，我们也在评估乳腺癌病例中末端导管小叶单位（TDLUs）的形态和分子特征，TDLUs是乳腺癌产生的结构。我们发现，与管腔肿瘤相比，TDLU复旧在含有核心基底表型（CBP）肿瘤的乳房中明显不那么明显。我们正在开展合作，利用其他研究的材料来证实和扩展这些发现。我们还测量和分析了150例波兰乳腺癌病例中正常TDLUs中的标志物表达，并将标志物数据与危险因素和临床特征相关联。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。我们之前曾报道过瓦尔登斯特罗姆巨球蛋白血症（WM）或淋巴浆细胞性淋巴瘤患者的一级亲属患淋巴恶性肿瘤的风险增加。我们最近证明亲属患髓系恶性肿瘤或实体瘤的风险没有增加。我们发现MGUS患者发生后续感染的风险增加（2倍，p 0.05）（随访5年和10年）。细菌和病毒感染都参与其中。m蛋白浓度较高的人风险最大。然而，感染的发展并不能预测MGUS患者随后发展为骨髓瘤、WM或相关恶性肿瘤的风险。在另一项研究中，既往感染、炎症性疾病和自身免疫性疾病与MGUS风险增加相关。自身免疫性疾病的家族史也与随后的MGUS相关，表明存在一些共同的易感性。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进展的生物标志物。