Genetic Epidemiology

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。一项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进行病例对照研究的试点研究正在计划中。来自意大利东北部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被用于评估黑色素皮质素-1受体（MC1R）基因（人类色素沉着的主要调节因子）和BRAF致癌基因的体细胞突变。在身体暴露在阳光下的区域和有限的慢性太阳损伤的黑色素瘤患者中，我们发现MC1R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。我们在一个独立的人群中证实了这种关联。收集了其他意大利人群的数据，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。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。我们计划在一系列组织样本和种系DNA中研究细胞周期、端粒和转导通路中多个基因突变的表达和存在，以探索通过痣参与黑色素瘤发展的机制。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。与人口控制相比，一级亲属患癌症风险的分析已经完成；结果报告正在进行中。一项儿童髓母细胞瘤的回顾性单机构研究的问卷调查数据显示，几乎没有证据表明髓母细胞瘤患者的亲属患癌症的风险增加。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。我们与波士顿麻省总医院放射肿瘤科合作，确定脊索瘤家族，以帮助绘制和确定脊索瘤易感基因。对家属的评估正在进行中。一个扩大的项目已经开发，以收集个人和家庭病史，颊细胞和肿瘤组织切片，从散发性脊索瘤患者来自美国各地。该项目将收集多达100名在任何年龄和解剖部位被诊断患有脊索瘤的患者。通过与耶鲁大学组织微阵列（TMA）核心设备的合作，我们已经成功地构建了1500个来自波兰乳腺癌研究的侵袭性肿瘤的TMA。我们用免疫组织化学（IHC）对这些肿瘤的一部分（N=842）进行了18个涉及激素生物合成、代谢和受体介导途径的分子标记的染色。对这些标志物的分析表明，乳腺癌的危险因素可能因分子亚型和以激素标志物共同表达为特征的激素途径而异。我们还使用新开发的自动定量分析（AQUA）对六种标记（er - α, er - β， PR, HER2， EGFR和CK5）的所有tma进行了染色。两种方法（AQUA和IHC）的比较表明，AQUA分析TMAs所代表的肿瘤提供了可靠的、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。我们将肿瘤亚型的危险因素异质性分析扩展到参与乳腺癌协会联盟（BCAC）的34项研究的汇总分析。除了分析浸润性肿瘤外，我们还测量了150例波兰乳腺癌病例中正常乳腺上皮细胞（终管小叶单位，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。肾细胞癌（RCC）的发病率在中欧和东欧是世界上最高的。von Hippel - lindo - hypoxia Inducible Factor （VHL-HIF）通路与肾癌的发生有关。我们研究了VHL-HIF通路中常见基因变异在散发性RCC和透明细胞RCC易感性中的作用。我们确定了与肾癌风险相关的VHL-HIF通路中基因的常见遗传变异。基因变异的评估已经完成；结果报告正在进行中。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淋巴样恶性肿瘤，并检测易患淋巴样恶性肿瘤的免疫相关和炎症性疾病（基于住院记录）。我们发现患淋巴浆细胞性淋巴瘤（LPL）的风险增加。Waldenstrom巨球蛋白血症（WM）与多种自身免疫性疾病的个人病史有关，特别是那些全身受累的疾病（OR=1.9, 95%CI: 1.3-2.7）。一些感染也与LPL-WM的风险增加有关。干燥综合征家族史也与LPL-WM相关（OR=5.0, 95%CI: 2.1-12.0），提示自身免疫性疾病和淋巴瘤的共同遗传易感。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。

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. A pilot study to follow-up patients from a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco is being planned. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy were used to evaluate the melanocortin-1 receptor (MC1R) gene, the major regulator of human pigmentation, and somatic mutations of the BRAF oncogene. In subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage, we found a strong association between MC1R germline variants and melanoma with somatic mutations in the BRAF oncogene. We confirmed this association in an independent population. Data from other Italian 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. 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, telomere, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. 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. Analyses to examine the risk of cancer among the first degree relatives compared to population controls have been completed; write-up of the results is in process. Examination of questionnaire data from a retrospective single institution study of childhood medulloblastoma showed little evidence for increased cancer risks among relatives of medulloblastoma patients. 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. We collaborated with the Department of Radiation Oncology, Massachusetts General Hospital, Boston, to identify chordoma families to help map and identify a chordoma susceptibility gene. Evaluation of the families is in progress. 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. The project will collect up to 100 patients diagnosed with chordoma at any age and anatomic site. In collaboration with Yale University Tissue Microarray (TMA) core facility, we have successfully built TMAs of 1,500 invasive tumors collected from the Polish Breast Cancer Study. We have immunohistochemically (IHC) stained a subset of these tumors (N=842) for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways. Analyses of these markers suggest that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We have also stained all TMAs for six markers (ER-alpha, ER-beta, PR, HER2, EGFR, and CK5) using a newly developed Automated Quantitative Analysis (AQUA). Comparison of the two approaches (AQUA and IHC) demonstrated 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 are expanding our analyses of risk factor heterogeneity by tumor subtypes to a pooled analysis of 34 studies participating in the Breast Cancer Association Consortium (BCAC). In addition to the analysis of invasive tumors, we are also measuring 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. Renal cell carcinoma (RCC) rates in Central and Eastern Europe are among the highest in the world. The von Hippel Lindau-Hypoxia Inducible Factor (VHL-HIF) pathway has been implicated in kidney cancer tumorigenesis. We investigated the role of common variants in genes in the VHL-HIF pathway in the susceptibility of sporadic RCC and clear cell RCC. We identified common genetic variants in genes in the VHL-HIF pathway associated with kidney cancer risk. Evaluation of the genetic variants has been completed; write-up of the results is in process. We are continuing to conduct studies using the Swedish linked registry data to define lymphoid malignancies that co-aggregate in families and to detect immune-related and inflammatory conditions (based on hospitalization records) that pre-dispose to lymphoid malignancies. We found an increased risk of lymphoplasmacytic lymphoma (LPL). Waldenstrom macroglobulinemia (WM) was associated with a personal history of several autoimmune diseases, especially those with systemic involvement (OR=1.9, 95%CI: 1.3-2.7). Several infections were also associated with increased risk of LPL-WM. A family history of Sjogren syndrome was also associated with LPL-WM (OR=5.0, 95%CI: 2.1-12.0) suggesting a common genetic predisposition 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.