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Biological processes, properties and molecular wiring diagrams of candidate low-penetrance breast cancer susceptibility genes

机译：低通透性乳腺癌易感基因的生物学过程，特性和分子接线图

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Background Recent advances in whole-genome association studies (WGASs) for human cancer risk are beginning to provide the part lists of low-penetrance susceptibility genes. However, statistical analysis in these studies is complicated by the vast number of genetic variants examined and the weak effects observed, as a result of which constraints must be incorporated into the study design and analytical approach. In this scenario, biological attributes beyond the adjusted statistics generally receive little attention and, more importantly, the fundamental biological characteristics of low-penetrance susceptibility genes have yet to be determined. Methods We applied an integrative approach for identifying candidate low-penetrance breast cancer susceptibility genes, their characteristics and molecular networks through the analysis of diverse sources of biological evidence. Results First, examination of the distribution of Gene Ontology terms in ordered WGAS results identified asymmetrical distribution of Cell Communication and Cell Death processes linked to risk. Second, analysis of 11 different types of molecular or functional relationships in genomic and proteomic data sets defined the "omic" properties of candidate genes: i/ differential expression in tumors relative to normal tissue; ii/ somatic genomic copy number changes correlating with gene expression levels; iii/ differentially expressed across age at diagnosis; and iv/ expression changes after BRCA1 perturbation. Finally, network modeling of the effects of variants on germline gene expression showed higher connectivity than expected by chance between novel candidates and with known susceptibility genes, which supports functional relationships and provides mechanistic hypotheses of risk. Conclusion This study proposes that cell communication and cell death are major biological processes perturbed in risk of breast cancer conferred by low-penetrance variants, and defines the common omic properties, molecular interactions and possible functional effects of candidate genes and proteins.
机译：背景技术针对人类癌症风险的全基因组关联研究（WGAS）的最新进展开始提供低渗透敏感性基因的部分清单。但是，这些研究中的统计分析由于所检查的大量遗传变异和观察到的微弱影响而变得复杂，因此必须将约束纳入研究设计和分析方法中。在这种情况下，超出调整后的统计数据的生物学特性通常很少受到关注，更重要的是，低渗透敏感性基因的基本生物学特性尚未确定。方法我们采用综合方法通过分析多种生物学证据来鉴定候选低渗透性乳腺癌易感基因，其特征和分子网络。结果首先，对有序WGAS结果中基因本体术语的分布进行检查，确定了与风险相关的细胞通讯和细胞死亡过程的不对称分布。其次，在基因组和蛋白质组学数据集中对11种不同类型的分子或功能关系的分析确定了候选基因的“组学”特性：i /肿​​瘤相对于正常组织的差异表达; ii /与基因表达水平相关的体细胞基因组拷贝数变化; iii /在诊断时跨年龄差异表达;和BRCA1扰动后iv /表达改变。最后，变体对种系基因表达影响的网络建模显示，新候选人之间以及与已知易感基因之间偶然发生的连接性比预期的更高，这支持了功能关系并提供了风险的机械假设。结论这项研究提出，细胞沟通和细胞死亡是低渗透性变异所导致的罹患乳腺癌风险的主要生物学过程，并定义了候选基因和蛋白质的共同组学特性，分子相互作用以及可能的功能效应。

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