Genetic Epidemiology of Cancer

癌症遗传流行病学

• 批准号: 7148007
• 负责人: Joan Ellen Bailey-Wilson
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 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/7148007
• 关键词: African American; American; Caribbean; Scandinavian; brca gene; breast neoplasms; cancer registry /resource; environment related neoplasm /cancer; family genetics; gene environment interaction; gene interaction; gene mutation; genetic markers; genetic polymorphism; genetic susceptibility; genotype; human subject; international cooperation; linkage mapping; lung neoplasms; melanoma; neoplasm /cancer genetics; prostate neoplasms; questionnaires; smoking

Dr. Bailey-Wilson has been working for over 20 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of this study is to identify a gene or genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana. Data collection is expected to continue for several more years. Dr. Bailey-Wilson is a founder of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) for the purpose of obtaining additional family data from a large group of collaborative investigators. A paper presenting GELCC results has been published in this fiscal year. About 60 families were genotyped for GWS markers at the Center for Inherited Disease Research (CIDR) and the first genome-wide significant linkage of a lung cancer susceptibility locus on chromosome 6q was published by us last year. A paper characterizing the effect of smoking in individuals predicted to be carriers of this 6q locus is in preparation. In this fiscal year, we have sequenced almost 100 candidate loci in this region and follow-up of these results is ongoing. A second set of families has been genotyped for the same GWS markers and analyses are ongoing. Dr. Bailey-Wilson and Dr. Doan have also applied their new propensity score method for including environmental risk factor data into non-parametric analyses (in LODPAL) to the original GWS data and a paper is in preparation. Another major aim of Dr. Bailey-Wilson?s research is to determine genetic risk factors in families with human prostate cancer. Papers published previously by our large group of collaborators have shown evidence of PRCA susceptibility genes in regions of chromosomes 1, 3p, 11q, 8 and X. These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scans. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region causing increased risk to prostate cancer and showed evidence that mutations in the MSR1 gene on chromosome 8 plays a role in prostate cancer risk. Families have been genotyped from several regions of the United States, Finland, Iceland and Sweden. Dr. Bailey-Wilson's group is currently analyzing the Finnish and African-American data. We have joined the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. Two meta-analysis papers were published by this group this year and another is in preparation. Dr. Bailey-Wilson is in charge of the Chromosome X meta-analysis. A paper detailing evidence of a significant association in our Finnish families to a narrow region on chromosome X has been published in this fiscal year. A linkage genome-wide scan of families from Finland, Sweden, and the U.S., including a significant number of African-American families from the African American Hereditary Prostate Cancer Consortium (AAHPC), of which Dr. Bailey-Wilson is a member, is ongoing in this fiscal year and will continue into the next year. A paper detailing the results of this genome wide scan in the Finnish families and another with results of a metaanalysis of several of these datasets have been published in the last fiscal year. Fine mapping markers were genotyped for the Finnish dataset to follow uo suggestive linkages, resulting in a paper published this year presenting strong evidence for a locus on chromosome 3p. We will continue to pursue evidence of a major locus in this region in these families. A new set of 43 extended Finnish prostate cancer pedigrees have been collected, power studies have been performed and genotyping for a genome wide scan has been started. Analyses will be performed in the next fiscal year. The GWS analysis of the African-American families described above has been completed and a paper presenting the results has been submitted. Another paper detailing the clinical characteristics of the African-American men in this dataset was published this year, as was a paper showing an association between a nonsense mutation in the gene EphB2 is associated with increased prostate cancer risk in African-American men. A linkage meta-analysis is now underway to combine our African-American families from the AAHPC with those available from the ICPCG in order to increase power to detect loci that are of particular importance in this racial group. A collaborative linkage study of breast cancer families that are not segregating mutations at either the BRCA1 or BRCA2 loci is ongoing. We are working with collaborators in Finland to follow-up candidate regions from our previous genome-wide linkage studies. Additional genotyping of SNP markers in several of these regions has been performed and association analyses are ongoing. A new dataset, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University, is now being studied. In this study, we are examining families with known mutations in BRCA1 and BRCA2 loci to attempt to detect modifier loci and gene-gene interactions. Genotyping for GWS markers has been completed in this fiscal year and these data will be analyzed in the next fiscal year. As an adjunct to the family-based studies of prostate and breast cancer described above, Dr. Bailey-Wilson is collaborating with Drs. Trent and Carpten of Tranlational Genomics, Drs. Cristina Leske and Barbara Nemesure of State University of New York at Stony Brook and Drs. Anselm Hennis and Lyndon Waterman of the University of the West Indies, in Barbados, on a study of the genetic epidemiology of prostate cancer and breast cancer in Barbados. These cancers occur at very high rates in the Barbadian population. Dr. Hennis' joint appointments in New York and Barbados have expedited this study. The pilot phase of a large case-control study is underway and a small adjunct family study is also being piloted. Questionnaires, study protocols and consent forms have been developed and are currently being used in Barbados, funded by a contract from NHGRI. This pilot data collection phase is expected to last for one more year, to be followed by the very large study. Dr. Bailey-Wilson is now the Project Officer for the data collection pilot study contract. Data collection is proceeding on schedule. The first analyses of these pilot data were performed this year; SNP loci were genotyped in the BRCA1 locus to determine if association to common polymorphisms at this locus could explain any large proportion of the breast cancer risk in this population. A manuscript is in preparation presenting these results. A collaborative linkage study of melanoma families that are not linked to known melanoma loci is ongoing. A genome wide scan of these samples yielded significant evidence of linkage of early-onset melanoma to one region of the genome at chromosome 1p22. Approximately 50 additional families from the Melanoma Consortium have been collected this year. Genotyping to exclude linkage to known loci is in progress. Appropriate families will be typed for a genome wide scan by CIDR and data will be merged with the data from the original scan to identify novel regions of interest. We continue to do follow up work in the 1p22 region identified in early onset cutaneous melanoma families. We have selected ~ 400 SNP markers to be genotyped in this region for a fine-mapping study. These data will be analyzed by Dr. Bailey-Wilson's group, using both linkage and association methods. In families that segregate both ocular and cutaneous melanoma we have typed 50 microsatellite and 1500 SNP markers in 3 regions. These data have been analyzed in this fiscal year and a manuscript is in preparation.

Bailey-Wilson博士已经工作了20多年，以检测肺癌和可能的基因和/或基因环境相互作用的遗传危险因素。这项研究的目的是确定有助于肺癌易感性的基因或基因。在这个财政年度，在路易斯安那州收集了家庭数据。数据收集预计将持续几年。 Bailey-Wilson博士是肺癌财团（GELCC）遗传流行病学的创始人，目的是从大量合作研究者那里获得其他家庭数据。在本财政年度发表了一篇介绍GELCC结果的论文。在遗传性疾病研究中心（CIDR）中，将约60个家庭用于GWS标记的基因分型，并于去年美国发表了肺癌易感性基因座的第一个肺癌易感性基因座的首个肺癌易感性基因座的显着联系。一份纸张表征了被预测是该6Q基因座载体的个体中吸烟作用的论文。在这个财政年度，我们在该地区对近100个候选基因座进行了测序，并且这些结果的随访正在进行中。第二组家庭已针对相同的GWS标记进行了基因分型，并且正在进行分析。 Bailey-Wilson博士和Doan博士还将其新的倾向分数方法应用于非参数分析（In LoDPAL）中的原始GWS数据中，并且正在准备一篇论文。 Bailey-Wilson博士的研究的另一个主要目的是确定人类前列腺癌家庭中的遗传危险因素。我们的大量合作者先前发表的论文显示了染色体1、3p，11q，11q，8和X区域中PRCA易感基因的证据。这些结果已随后对这些地区和其他地区的标记进行了深入的连锁分析，在其他地区显示了最初的基因组扫描中有一些链接的微微证据。以前，我们的小组鉴定出核糖核酸酶-L（RNASEL）基因的突变是我们1染色体连接区域中的基因座，导致前列腺癌的风险增加，并显示出证据表明，8号染色体上的MSR1基因突变在前列腺癌风险中起作用。从美国，芬兰，冰岛和瑞典的几个地区进行了基因分型。 Bailey-Wilson博士目前正在分析芬兰和非裔美国人数据。我们已经加入了国际前列腺癌遗传学联盟（ICPCG），试图更快地定位前列腺癌基因座。该小组今年发表了两篇荟萃分析论文，另一篇正在准备。 Bailey-Wilson博士负责X染色体X元分析。本财政年度发表了一篇论文，详细介绍了芬兰家庭与X染色体X狭窄地区的狭窄地区的重要关联的证据。来自芬兰，瑞典和美国家庭的全基因组扫描，包括来自非裔美国人遗传前列腺癌财团（AAHPC）的大量非裔美国人家庭（AAHPC），Bailey-Wilson博士是成员，在这个财政年度正在进行，并将持续到下一年。一篇论文详细介绍了芬兰家庭中这种基因组广泛扫描的结果，另一篇是在上一个财政年度发表的，其中几个数据集的荟萃分析的结果。为芬兰数据集遵循UO暗示性的联系，对精细的映射标记进行了基因分型，导致今年发表的一篇论文提供了关于3p染色体的基因座的有力证据。我们将继续追求这些家庭中该地区一个主要轨迹的证据。已经收集了一组新的43套芬兰前列腺癌扩展的癌症，已经进行了功率研究，并开始进行基因组广泛扫描的基因分型。分析将在下一个财政年度进行。上述非裔美国人家庭的GWS分析已经完成，并提交了一份介绍结果的论文。另一篇论文详细介绍了该数据集中非裔美国人的临床特征，这是今年发表的，这是一篇论文，显示基因EPHB2中胡说八道突变之间存在关联与非裔美国人男性前列腺癌风险的增加有关。现在正在进行一项链接荟萃分析，以将我们的非裔美国人家庭与ICPC的可获得的链接结合起来，以增加在这个种族群体中特别重要的基因座的能力。 对BRCA1或BRCA2基因座的乳腺癌家族的合作联系研究正在进行中。我们正在与芬兰的合作者合作，从我们以前的全基因组联系研究中进行后续候选地区。在其中一些区域中，SNP标记的其他基因分型已经进行了，并且正在进行关联分析。 与温德伯研究所的雷切尔·埃尔斯沃思（Rachel Ellsworth）博士合作的新数据集和博士。克雷顿大学的亨利·林奇（Henry Lynch）和帕特里斯·沃森（Patrice Watson）现在正在研究。在这项研究中，我们正在研究BRCA1和BRCA2基因座中已知突变的家庭，以试图检测修饰的基因座和Gene-Gene相互作用。 GWS标记的基因分型已经在本财政年度完成，这些数据将在下一个财政年度进行分析。 作为上述前列腺和乳腺癌家庭研究的辅助，Bailey-Wilson博士正在与Drs合作。 Trent and Carpten of tranlational Genomics，Drs。纽约州立大学Stony Brook and Drs的Cristina Leske和Barbara Nemesure。西印度群岛大学的安塞尔姆·亨尼斯（Anselm Hennis）和林登·沃特曼（Lyndon Waterman）在巴巴多斯（Barbados）研究了巴巴多斯前列腺癌和乳腺癌的遗传流行病学。这些癌症的发生率很高。亨尼斯博士在纽约和巴巴多斯的联合任命加快了这项研究。大型病例对照研究的试验阶段正在进行中，并且还试行了一项小型辅助家庭研究。问卷，研究方案和同意书已开发，目前正在巴巴多斯使用，并由NHGRI的合同资助。该试验数据收集阶段预计将持续一年，然后进行非常大型的研究。 Bailey-Wilson博士现在是数据收集试点研究合同的项目官员。数据收集按计划进行。这些试验数据的首次分析是今年进行的。在BRCA1基因座中对SNP基因座进行了基因分型，以确定该基因座的共同多态性是否可以解释该人群中任何很大一部分乳腺癌的风险。手稿正在准备这些结果。 一项与已知黑色素瘤基因座无关的黑色素瘤家族的合作联系研究正在进行中。这些样品的基因组广泛扫描提供了在1p22染色体时早期黑色素瘤与基因组一个区域连接的重要证据。今年已经收集了来自黑色素瘤财团的大约50个家庭。基因分型排除与已知基因座的联系正在进行中。将通过CIDR为基因组范围扫描键入合适的家庭，并将数据与原始扫描的数据合并，以识别新颖的感兴趣区域。我们继续在早期发作皮肤黑色素瘤家庭中确定的1P22地区进行后续工作。我们选择了约400个SNP标记，以在该区域进行基因分型进行精细映射研究。这些数据将使用链接和关联方法由Bailey-Wilson博士组分析。在分离眼和皮肤黑色素瘤的家族中，我们在3个区域键入了50个微卫星和1500个SNP标记。这些数据已在本财政年度进行了分析，并正在准备手稿。