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。最近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。此外，计划对地中海国家和适当对照的黑色素瘤病例进行全基因组关联研究。已收集黑色素瘤组织标本，并计划分析黑色素瘤病变与日晒、身体部位、痣数、易感基因和分子改变的关系。我们已经选择了一个由60个候选基因组成的小组，用于黑色素瘤的发展和进展，我们目前正在使用该基因小组测试从200个FFPE病变中提取的DNA。基于结果，我们可以将分析扩展到更大的黑色素瘤病变样本，以更准确地对该疾病进行分子分类。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。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。使用从本研究招募的100例散发性脊索瘤患者中提取的颊细胞DNA，我们确定了与疾病风险相关的T基因中几种常见和罕见的变异。我们的发现为T基因的遗传变异在家族性和散发性脊索瘤发病机制中的重要性提供了更多的证据。目前，我们正在使用全外显子组测序来鉴定无T重复脊索瘤家族以及散发性脊索瘤病例的其他易感基因。我们还与中国北京的肿瘤医院合作，收集中国脊索瘤患者的种系DNA和脊索瘤肿瘤组织，以跟踪我们从外显子组测序项目中发现的变异。人们越来越认识到正常微生物组的改变在人类疾病中发挥作用。采用美国国立卫生研究院人类微生物组计划的方案，我们正在进行初步研究，以评估吸烟者和非吸烟者之间口腔微生物组的差异。试点研究正在与罗切斯特大学医学和牙科学院的研究人员合作进行。使用我们从波兰乳腺癌研究和乳腺癌协会联盟（BCAC）收集的数据，我们证明了乳腺癌的危险因素和终端导管小叶单位（TDLUs）的形态和分子特征，乳腺癌的发生结构，因分子亚型而异。此外，我们发现，胎次相关的分子变化在er阳性肿瘤的乳腺癌患者中得以保留，而在er阴性肿瘤患者中则被破坏，这一发现可能部分解释了在这两种肿瘤亚型中观察到的胎次差异效应。我们目前正在分析表达谱数据，以确定TDLU对合和奇偶的分子特征。最近，我们与亚洲国家的临床医生和流行病学家一起启动了几个乳腺癌项目，研究亚洲女性的乳腺癌。使用从马来西亚沙捞越收集的数据，我们发现马来西亚妇女中早发性和er阴性肿瘤的过度代表主要是由于晚发性er阳性肿瘤的发病率不成比例地低，而不是er阴性癌症的绝对增加。为了扩展这一发现，我们使用了从几个亚洲国家（新加坡、台湾、香港、中国、韩国）获得的癌症登记数据，并报告说，在调整了时期和队列效应之后，乳腺癌的年龄效应在亚洲和西方女性之间可能比以前认识到的更相似。最近，我们在香港开展了一项新的基于组织的乳腺癌研究，我们计划从多达1000例乳腺癌病例中收集乳腺肿瘤和邻近正常组织，目的是确定与香港中国女性乳腺癌亚型的风险和临床因素相关的分子变化。我们正在继续开展血液恶性肿瘤的研究，使用瑞典相关登记数据来补充GEB的家庭研究。我们使用瑞典注册数据库进行了一项研究，以确定MPN诊断后的生存是否与患者是家族性还是散发性有关。我们没有发现家族性患者与散发性患者的生存差异。我们关于家族性和散发性MPN患者相似生存率的新发现与早期关于家族性和散发性MPN患者相似临床表现和血栓形成率的报道是一致的。使用类似的方法评估生存率，我们发现家族性WM/LPL患者的生存率明显低于散发性患者。这些结果支持遗传易感性使患者易患更严重的LPL/WM的理论。霍奇金淋巴瘤（HL）患者具有典型的T细胞功能免疫缺陷，最初是通过对某些感染的易感性增加来确定的。使用我们的瑞典注册数据，我们使用无条件逻辑回归评估了与广泛的感染和炎症状况相关的HL的后续风险。既往任何报告的感染史都与HL的风险显著增加相关。我们的研究结果表明，潜在的免疫缺陷是HL的主要现象。另外，某些感染因子可能是HL的潜在诱因。

Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Recent 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. Moreover, a genome-wide association study of melanoma cases from Mediterranean countries and appropriate controls is planned. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure, body site, nevi count, susceptibility genes and molecular alterations is planned. We have selected a panel of 60 candidate genes for melanoma development and progression and we are currently testing the DNA extracted from 200 FFPE lesions using this gene panel. Based on the results, we may extend the analyses to a larger sample of melanoma lesions for a more accurate molecular classification of the disease. 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. 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. Using buccal cell DNA extracted from 100 sporadic chordoma patients we have recruited in this study, we identified several common and rare variants in the T gene that are related to disease risk. Our findings provide more evidence for the importance of genetic variations in the T gene in the pathogenesis of both familial and sporadic chordoma. Currently, we are using whole-exome sequencing to identify additional susceptibility genes in chordoma families without T duplication as well as sporadic chordoma cases. We are also collaborating with cancer hospitals in Beijing, China to collect germline DNA andchordoma tumor tissues from Chinese chordoma patients to follow up on variants we identify from the exome sequencing project. Alterations in the normal microbiome are increasingly recognized to play a role in human disease. Using protocols adapted from the NIH Human Microbiome Project, we are conducting pilot studies to evaluate differences in the oral microbiome between smokers and nonsmokers. Pilot studies are being conducted in collaboration with investigators from the School of Medicine and Dentistry, University of Rochester. Using data we collected from the Polish Breast Cancer Study and breast cancer association consortium (BCAC), we demonstrated that risk factors for breast cancer and morphology and molecular characteristics of terminal duct lobular units (TDLUs), the structures from which breast cancers arise, varied by molecular subtypes. In addition, we found that parity-related molecular changes were preserved in breast cancer patients with ER-positive tumors but disrupted in patients with ER-negative tumors, a finding that may partially account for the observed differential effect of parity in these two tumor subtypes. We are currently analyzing the expression profiling data to identify molecular signatures for TDLU involution and parity. Recently, we initiated several breast cancer projects with clinicians and epidemiologists in Asian countries to study breast cancer among Asian women. Using data collected from Sarawak, Malaysia, we showed that the overrepresentation of early-onset and ER-negative tumors among Malaysian women was largely due to the disproportionally lower incidence of late-onset ER-positive tumors rather than an absolute increase in ER-negative cancers. To extend the finding, we used cancer registry data obtained from several Asian countries (Singapore, Taiwan, Hong Kong, China, Korea) and reported that, after the adjustment of period and cohort effects, the age effects of breast cancer may be more similar between Asian and Western women than previously recognized. Recently, we have developed a new tissue-based breast cancer study in Hong Kong, in which we plan to collect breast tumor and adjacent normal tissues from up to 1,000 breast cancer cases with the goal of identifying molecular changes that are related to risk and clinical factors for breast cancer subtypes among Chinese women in Hong Kong. We are continuing to conduct studies of hematologic malignancies using the Swedish linked registry data to complement the family studies in GEB. We conducted a study using linked Swedish registry databases to determine whether survival after MPN diagnosis was related to whether the patient was familial or sporadic. We did not find a survival difference in familial patients compared to sporadic. Our novel findings on similar survival in familial and sporadic MPN patients are consistent with earlier reports on comparable clinical presentation and rate of thrombosis in familial and sporadic MPN patients. Using similar methodology to evaluate survival, we found that familial WM/LPL patients had significantly worse survival than did sporadic patients. These results support the theory that genetic susceptibility predisposes patients to a more severe form of LPL/WM.Patients with Hodgkin lymphoma (HL) have a well-characterized immune deficiency of T cell function, originally identified by increased susceptibility to certain infections. Using our Swedish registry data, we evaluated the subsequent risk of HL in relation to a broad range of infectious and inflammatory conditions, using unconditional logistic regression. A previous history of any reported infection was associated with a significantly increased risk of HL... Our results suggest that underlying immune deficiency is a primary phenomenon in HL. Alternatively, certain infectious agents may be potential HL triggers.