Laboratory of Innovative Medicine, School of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia.
PeerJ. 2022 Aug 11;10:e13860. doi: 10.7717/peerj.13860. eCollection 2022.
Cancer driver genes are usually ranked by mutation frequency, which does not necessarily reflect their driver strength. We hypothesize that driver strength is higher for genes preferentially mutated in patients with few driver mutations overall, because these few mutations should be strong enough to initiate cancer.
We propose formulas for the Driver Strength Index (DSI) and the Normalized Driver Strength Index (NDSI), the latter independent of gene mutation frequency. We validate them using TCGA PanCanAtlas datasets, established driver prediction algorithms and custom computational pipelines integrating SNA, CNA and aneuploidy driver contributions at the patient-level resolution.
DSI and especially NDSI provide substantially different gene rankings compared to the frequency approach. ., NDSI prioritized members of specific protein families, including G proteins , and , isocitrate dehydrogenases and , and fibroblast growth factor receptors and . KEGG analysis shows that top NDSI-ranked genes comprise pathway, pathway, and pathway.
Our indices are able to select for driver gene attributes not selected by frequency sorting, potentially for driver strength. Genes and pathways prioritized are likely the strongest contributors to cancer initiation and progression and should become future therapeutic targets.
癌症驱动基因通常按突变频率排序，但这并不一定反映其驱动强度。我们假设，在总体驱动突变较少的患者中优先发生突变的基因，其驱动强度更高，因为这些少数突变应该足够强大，足以引发癌症。
我们提出了驱动强度指数（DSI）和归一化驱动强度指数（NDSI）的公式，后者不依赖于基因突变频率。我们使用 TCGA PanCanAtlas 数据集、已建立的驱动预测算法以及整合 SNA、CNA 和患者水平的非整倍体驱动贡献的自定义计算管道对其进行了验证。
DSI 特别是 NDSI 与频率方法相比提供了截然不同的基因排名。例如，NDSI 优先考虑了特定蛋白质家族的成员，包括 G 蛋白、异柠檬酸脱氢酶和成纤维细胞生长因子受体。KEGG 分析表明，排名最高的 NDSI 基因包括代谢途径、癌症途径和精氨酸生物合成途径。
我们的指数能够选择频率排序未选择的驱动基因属性，可能是驱动强度。优先考虑的基因和途径可能是癌症发生和进展的最强贡献者，应该成为未来的治疗靶点。
