Feilotter Harriet E, Michel Claire, Uy Paolo, Bathurst Lauren, Davey Scott
Departments of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada; Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Departments of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada; Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario, Canada.
PLoS One. 2014 Jun 20;9(6):e100068. doi: 10.1371/journal.pone.0100068. eCollection 2014.
The assessment of BRCA1 and BRCA2 coding sequences to identify pathogenic mutations associated with inherited breast/ovarian cancer syndrome has provided a method to identify high-risk individuals, allowing them to seek preventative treatments and strategies. However, the current test is expensive, and cannot differentiate between pathogenic variants and those that may be benign. Focusing only on one of the two BRCA partners, we have developed a biological assay for haploinsufficiency of BRCA1. Using a series of EBV-transformed cell lines, we explored gene expression patterns in cells that were BRCA1 wildtype compared to those that carried (heterozygous) BRCA1 pathogenic mutations. We identified a subset of 43 genes whose combined expression pattern is a sensitive predictor of BRCA1 status. The gene set was disproportionately made up of genes involved in cellular differentiation, lending credence to the hypothesis that single copy loss of BRCA1 function may impact differentiation, rendering cells more susceptible to undergoing malignant processes.
对BRCA1和BRCA2编码序列进行评估以识别与遗传性乳腺癌/卵巢癌综合征相关的致病突变,为识别高危个体提供了一种方法,使他们能够寻求预防性治疗和策略。然而,目前的检测成本高昂,且无法区分致病变体和可能为良性的变体。仅聚焦于两个BRCA基因之一,我们开发了一种针对BRCA1单倍剂量不足的生物学检测方法。利用一系列EBV转化的细胞系,我们探究了BRCA1野生型细胞与携带(杂合)BRCA1致病突变的细胞的基因表达模式。我们鉴定出一个由43个基因组成的子集,其组合表达模式是BRCA1状态的敏感预测指标。该基因集不成比例地由参与细胞分化的基因组成,这支持了以下假设:BRCA1功能的单拷贝缺失可能影响分化,使细胞更容易发生恶性过程。