Genetic epidemiology of breast cancer

对BRCA1或BRCA2基因座没有分离突变的乳腺癌家族的协作性连锁研究正在进行中。芬兰、瑞典和冰岛的合作者正在与NHGRI合作，将更多的家庭添加到数据集中。对这些样本进行了几个候选区域的基因分型和全基因组扫描。连锁分析正在进行中，2000年初在PNAS上发表了一篇论文，提出了在BRCA2基因座约20 cM处增加一个基因座(BRCA3)的可能性。阳性区域的精细测绘也在进行中。我们已经进行了额外的突变检测、基因分型和分析，以表明13q21-22处的阳性连锁证据不太可能是由于未检测到的BRCA2家族污染了我们的样本。那些似乎与BRCA1、BRCA2或这个新的BRCA3基因座没有关联的家族已经为标记基因座的基因组扫描小组进行了基因分型。有几个地区显示了一些联系的证据，目前正在对联系证据最强的地区进行精细的测绘研究。本财年还发表了一篇详细介绍这些结果的论文。这个项目正在进行中。对其中几个地区的SNP标记进行了额外的基因分型，分析正在进行中。 第二个项目涉及开发更好的数学模型来预测BRCA1或BRCA2突变的携带者的概率，该项目是与比萨大学的Silvano Presciuttini博士和Fabio Marroni博士以及约翰霍普金斯大学彭博公共卫生学院的Giovanni Parmigiani博士合作进行的，并在本财年发表了一篇介绍这些结果的论文。 今年，与温伯研究所的雷切尔·埃尔斯沃斯博士、克雷顿大学的亨利·林奇博士和帕特里斯·沃森博士合作，开展了一个新的项目。在这项研究中，我们将检查BRCA1和BRCA2基因座已知突变的家系，试图检测修饰基因座和基因-基因相互作用。贝利-威尔逊博士和她的工作人员在本财年与这些研究人员在研究设计、电力问题和数据管理方面进行了合作。目前正在对这些家庭进行GWS标记的基因分型，这些数据将在下一财年进行分析。

A collaborative linkage study of breast cancer families that are not segregating mutations at either the BRCA1 or BRCA2 loci is ongoing. Collaborators in Finland, Sweden and Iceland are working together with NHGRI to add more families to the data set. Genotyping of several candidate regions and a genome wide scan have been performed on these samples. Linkage analysis is ongoing and a paper was published in PNAS in early 2000 suggesting the possibility of an additional locus (BRCA3) about 20 cM from the BRCA2 locus. Fine mapping of positive regions is also ongoing. We have performed additional mutation detection, genotyping and analysis to show that the positive linkage evidence at 13q21-22 is not likely to be due to contamination of our sample by undetected BRCA2 families. Families that did not appear linked to BRCA1, BRCA2 or this novel BRCA3 locus have been genotyped for a genome scan panel of marker loci. Several regions showed some evidence for linkage and the regions with the strongest evidence for linkage are currently being followed up with fine mapping studies. A paper detailing these results has also been published in this fiscal year. This project is ongoing. Additional genotyping of SNP markers in several of these regions has been performed and analyses are ongoing. A second project involving development of better mathematical models for predicting probability of being a carrier of a BRCA1 or BRCA2 mutation was performed in collaboration with Drs. Silvano Presciuttini and Fabio Marroni of the University of Pisa and Dr. Giovanni Parmigiani of Johns Hopkins Bloomberg School of Public Health and a paper was published this fiscal year presenting these results. A new project has been undertaken this year, in collaboration with Dr. Rachel Ellsworth of the Windber Research Institute, and Drs. Henry Lynch and Patrice Watson of Creighton University. In this study, we will examine families with known mutations in BRCA1 and BRCA2 loci to attempt to detect modifier loci and gene-gene interactions. Dr. Bailey-Wilson and her staff have worked with these investigators on study design, power issues and data management in this fiscal year. The families are currently being genotyped for GWS markers and these data will be analyzed in the next fiscal year.