Kote-Jarai Zsofia, Williams Richard D, Cattini Nicola, Copeland Maria, Giddings Ian, Wooster Richard, tePoele Robert H, Workman Paul, Gusterson Barry, Peacock John, Gui Gerald, Campbell Colin, Eeles Ros
Translational Cancer Genetics, The Institute of Cancer Research, Sutton, Surrey, UK.
Clin Cancer Res. 2004 Feb 1;10(3):958-63. doi: 10.1158/1078-0432.ccr-1067-3.
The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated.
High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones.
Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (approximately 85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51.
The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.
研究种系BRCA1突变的存在对辐射诱导DNA损伤后正常乳腺成纤维细胞基因表达的影响。
采用高密度cDNA微阵列技术，比较9名杂合BRCA1突变携带者的成纤维细胞与5名无个人或家族癌症病史的对照样本对DNA损伤的差异反应。对成纤维细胞培养物进行辐射，并使用代表5603个IMAGE克隆的cDNA微阵列的强度比比较其表达谱。
类比较和类预测分析表明，BRCA1突变携带者与对照有很高的概率（约85%）可以区分。微阵列的显著性分析和支持向量机分类器确定了根据样本突变状态区分样本的基因集。这些基因包括已知与BRCA1相互作用的基因，如CDKN1B、ATR和RAD51。
这项初步研究的结果表明，杂合BRCA1突变携带者的正常细胞在对DNA损伤的反应中表现出与对照不同的基因表达谱。将这一初步结果应用于其他细胞类型可能会导致开发一种用于BRCA1突变状态的功能检测方法。
