Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes.
Malignancy of Cancers and Synthetic Lethal Interactions Associated With Mutations of Cancer Driver Genes.
复制标题
癌症的恶性程度和与癌症驱动基因突变相关的综合致死相互作用
DOI：
10.1097/md.0000000000002697
复制
发表时间：
2016-02
期刊：
影响因子：
1.6
通讯作者：
He KY
中科院分区：
文献类型：
--
作者：
Wang X;Zhang Y;Han ZG;He KY
摘要 癌症驱动基因的突变状态可能与癌症不同程度的恶性程度相关。倍增时间和多药耐药性是反映癌细胞恶性程度的2个表型。由于大多数癌症驱动基因很难靶向，因此鉴定其合成致死伴侣可能是治疗具有相关突变的癌症的可行方法。对合成致死伴侣的全基因组筛选成本高昂且劳动强度大。因此，一种有助于识别候选基因以进行重点合成致死RNAi筛选的计算方法将加速新型抗癌药物的发现。我们在这项研究中使用了几种公开的癌细胞系和肿瘤组织基因组数据。我们比较了一些癌症驱动基因突变的NCI-60细胞系和没有突变的NCI-60细胞系之间的倍增时间和多药耐药性。通过将癌细胞系中的基因表型值与相关突变和野生型背景进行比较，我们确定了癌症驱动基因 APC、KRAS、BRAF、PIK3CA 和 TP53 的一些候选合成致死基因。此外，我们通过实验验证了我们预测的一些合成致死关系。我们报道了一些癌症驱动基因的突变，例如APC、KRAS或PIK3CA等一些癌症驱动基因的突变可能与癌症增殖或耐药性相关。我们分别鉴定了 APC、KRAS、BRAF、PIK3CA 和 TP53 的 40、21、5、43 和 18 个潜在合成致死基因。我们发现，一些潜在的合成致死基因在其合成致死伙伴和野生型对应基因发生突变的癌症中表现出显着更高的表达。此外，我们的实验证实了几种合成致死关系，这是我们方法的新发现。我们通过实验验证了我们预测的部分合成致死关系。我们计划进行进一步的实验来验证本研究预测的其他合成致死关系。我们的计算方法实现了识别癌症驱动基因的候选合成致死伙伴，以进行多线证据的进一步实验筛选，从而有助于抗癌药物的开发。
AbstractThe mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate the other synthetic lethal relationships predicted by this study.Our computational methods achieve to identify candidate synthetic lethal partners to cancer driver genes for further experimental screening with multiple lines of evidences, and therefore contribute to development of anticancer drugs.