Genetic epidemiology of breast cancer

一项针对在BRCA1或BRCA2位点均未分离突变的乳腺癌家族的合作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，在数据集中增加更多的家庭。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上发表的一篇论文表明，在BRCA2位点约20 cM处可能存在另一个位点（BRCA3）。正区域的精细映射也在进行中。我们进行了额外的突变检测、基因分型和分析，以表明13q21-22的阳性连锁证据不太可能是由于我们的样本被未检测到的BRCA2家族污染。与BRCA1、BRCA2或这种新型BRCA3位点没有关联的家族已经通过标记位点的基因组扫描面板进行了基因分型。有几个地区显示出一些联系的证据，目前正在对联系证据最充分的地区进行详细的绘图研究。本财政年度还发表了一份详细说明这些结果的文件。这个项目正在进行中。已经对其中几个区域的SNP标记进行了额外的基因分型，分析正在进行中。

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.