DNA损伤反应和细胞周期通路在乳腺癌分类中的价值
An evaluation of DNA-damage response and cell-cycle pathways for breast cancer classification
摘要：
乳腺癌的准确亚型或分类对于确保患者的适当治疗以及理解驱动这种疾病的分子机制非常重要。虽然文献中提出了几种基因特征来对乳腺肿瘤进行分类，但这些特征显示出非常低的重叠、不同的分类性能，并且与这些肿瘤的潜在生物学没有太大相关性。在这里，我们评估DNA损伤反应（DDR）和细胞周期途径，这是在相当大的比例的乳腺肿瘤中涉及的关键途径，其有用性和能力，在乳腺肿瘤亚型。我们认为，基于这两种途径对乳腺肿瘤进行分型，可能会导致对驱动这些肿瘤的分子机制的重要见解。在这里，我们进行了系统的评估DDR和细胞周期途径的亚型乳腺肿瘤到五个已知的内在亚型。同源异型化（HR）途径在乳腺肿瘤亚型中表现出最好的性能，表明HR基因强烈参与所有乳腺肿瘤。基于途径的签名和两个标准基因签名的比较支持使用已知的途径进行乳腺肿瘤亚型分型。此外，对这些标准基因特征的评估表明，乳腺肿瘤亚型、预后和生存估计都密切相关。最后，我们通过组合（联合）所有基因并进行严格的特征选择来构建一个包罗万象的超级签名，并发现它在分类和预后价值方面相当准确和稳健。采用DDR和细胞周期途径进行乳腺肿瘤亚型分型实现了稳健和准确的乳腺肿瘤亚型分型，并且构建包含来自这些分子途径以及临床方面的基因的特征选择混合物的超级签名在临床实践中是有价值的。
英文摘要：
Accurate subtyping or classification of breast cancer is important for ensuring proper treatment of patients and also for understanding the molecular mechanisms driving this disease. While there have been several gene signatures proposed in the literature to classify breast tumours, these signatures show very low overlaps, different classification performance, and not much relevance to the underlying biology of these tumours. Here we evaluate DNA-damage response (DDR) and cell cycle pathways, which are critical pathways implicated in a considerable proportion of breast tumours, for their usefulness and ability in breast tumour subtyping. We think that subtyping breast tumours based on these two pathways could lead to vital insights into molecular mechanisms driving these tumours. Here, we performed a systematic evaluation of DDR and cell-cycle pathways for subtyping of breast tumours into the five known intrinsic subtypes. Homologous Recombination (HR) pathway showed the best performance in subtyping breast tumours, indicating that HR genes are strongly involved in all breast tumours. Comparisons of pathway based signatures and two standard gene signatures supported the use of known pathways for breast tumour subtyping. Further, the evaluation of these standard gene signatures showed that breast tumour subtyping, prognosis and survival estimation are all closely related. Finally, we constructed an all-inclusive super-signature by combining (union of) all genes and performing a stringent feature selection, and found it to be reasonably accurate and robust in classification as well as prognostic value. Adopting DDR and cell cycle pathways for breast tumour subtyping achieved robust and accurate breast tumour subtyping, and constructing a super-signature which contains feature selected mix of genes from these molecular pathways as well as clinical aspects is valuable in clinical practice.
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