Walker Logan C, Waddell Nic, Ten Haaf Anette, Grimmond Sean, Spurdle Amanda B
Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, QLD, Australia.
Breast Cancer Res Treat. 2008 Nov;112(2):229-36. doi: 10.1007/s10549-007-9848-5. Epub 2007 Dec 20.
Germline mutations in BRCA1 or BRCA2 confer an increased lifetime risk of developing breast or ovarian cancer, but variable penetrance suggests that cancer susceptibility is influenced in part by modifier genes. Microarray expression profiling was conducted for 69 irradiated lymphoblastoid cell lines derived from healthy controls, or from cancer-affected women with a strong family history of breast and ovarian cancer carrying pathogenic mutations in BRCA1 or BRCA2, or with no BRCA1/2 mutations (BRCAX). Genes discriminating between BRCA1, BRCA2 or BRCAX and controls were stratified based on irradiation response and/or cell cycle involvement. Gene lists were aligned against genes tagged with single nucleotide polymorphisms (SNPs) determined by the Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Whole Genome Association Scan to be nominally associated with breast cancer risk. Irradiation responsive genes whose expression correlated with BRCA1 and/or BRCA2 mutation status were more likely to be tagged by risk-associated SNPs in the CGEMS dataset (BRCA1, P = 0.0005; BRCA2, P = 0.01). In contrast, irradiation responsive genes correlating with BRCAX status were not enriched in the CGEMS dataset. Classification of expression data by involvement in cell cycle processes did not enrich for genes tagged by risk-associated SNPs, for BRCA1, BRCA2 or BRCAX groups. Using a novel combinatorial approach, we have identified a subset of irradiation responsive genes as high priority candidate BRCA1/2 modifier genes. Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved.
BRCA1或BRCA2的种系突变会增加患乳腺癌或卵巢癌的终生风险，但可变的外显率表明癌症易感性部分受修饰基因影响。对69个辐射淋巴母细胞系进行了微阵列表达谱分析，这些细胞系来自健康对照，或来自有乳腺癌和卵巢癌家族病史且携带BRCA1或BRCA2致病突变的癌症患者，或无BRCA1/2突变（BRCAX）的癌症患者。根据辐射反应和/或细胞周期参与情况，对区分BRCA1、BRCA2或BRCAX与对照的基因进行分层。将基因列表与通过癌症易感性基因标记（CGEMS）乳腺癌全基因组关联扫描确定的与乳腺癌风险名义上相关的单核苷酸多态性（SNP）标记的基因进行比对。其表达与BRCA1和/或BRCA2突变状态相关的辐射反应基因在CGEMS数据集中更有可能被风险相关SNP标记（BRCA1，P = 0.0005；BRCA2，P = 0.01）。相比之下，与BRCAX状态相关的辐射反应基因在CGEMS数据集中未富集。按细胞周期过程参与情况对表达数据进行分类，对于BRCA1、BRCA2或BRCAX组，未富集被风险相关SNP标记的基因。使用一种新的组合方法，我们确定了一组辐射反应基因作为BRCA1/2修饰基因的高优先级候选基因。类似的方法可用于识别与外源性刺激相互作用以引起或改变任何疾病的基因和潜在遗传风险因素，而无需事先了解所涉及的途径。
