Translating bioinformatics in oncology: guilt-by-profiling analysis and identification of KIF18B and CDCA3 as novel driver genes in carcinogenesis
Translating bioinformatics in oncology: guilt-by-profiling analysis and identification of KIF18B and CDCA3 as novel driver genes in carcinogenesis
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DOI：
10.1093/bioinformatics/btu586
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发表时间：
2015-01-15
期刊：
影响因子：
5.8
通讯作者：
Teufel, Andreas
中科院分区：
文献类型：
--
作者：
Itzel, Timo;Scholz, Peter;Teufel, Andreas
动机：在传统的微阵列分析中，共调控基因没有被识别出来，但理论上可能在功能上紧密相连[内疚-联想(GBA)，内疚-侧写]。因此，生物信息学的内疚-侧写/关联分析方法还没有应用于大规模的癌症生物学。我们使用皮尔逊相关系数(CC)分析了163个不同癌症实体的2158个完整的癌症转录本，分析了它们的基因表达相似性。随后，将428个高共调控基因(垂直条带CC，垂直条带=0.8)进行无监督聚类，以获得小的共调控网络。一个包含61个密切协同调控基因的主要亚网络显示出癌症生物功能的高度显著丰富。除Kinesin家族成员18B(KIF18B)和细胞分裂周期相关基因3(CDCA3)外，其他基因均与肿瘤生物学相关。因此，我们独立分析了它们在多种肿瘤中的差异调控，发现在肝癌、乳腺癌、肺癌、卵巢癌和肾癌中它们的调控严重失调，从而证明了我们的GBA假说。KIF18B和CDCA3在肝癌细胞中的过表达和随后的微阵列分析显示，中央细胞周期调控基因显著解除调控。RT-PCR和增殖实验一致地证实了这两个基因在细胞周期进展中的作用。最后，在三个独立的肝癌队列和其他几个肿瘤中，被识别的KIF18B和CDCA3依赖的预测因子的预后意义被证明(P=0.01，P=0.04)。综上所述，我们证明了大规模的内疚侧写/关联策略在肿瘤学中的有效性。我们发现了两个新的癌基因，并对它们进行了功能鉴定。下游预测因子对肝细胞癌和许多其他肿瘤的强大预后重要性表明了我们的研究结果的临床相关性。
Motivation: Co-regulated genes are not identified in traditional micro-array analyses, but may theoretically be closely functionally linked [guilt-by-association (GBA), guilt-by-profiling]. Thus, bioinformatics procedures for guilt-by-profiling/association analysis have yet to be applied to large-scale cancer biology.We analyzed 2158 full cancer transcriptomes from 163 diverse cancer entities in regard of their similarity of gene expression, using Pearson's correlation coefficient (CC). Subsequently, 428 highly co-regulated genes (vertical bar CC vertical bar >= 0.8) were clustered unsupervised to obtain small co-regulated networks. A major subnetwork containing 61 closely co-regulated genes showed highly significant enrichment of cancer bio-functions. All genes except kinesin family member 18B (KIF18B) and cell division cycle associated 3 (CDCA3) were of confirmed relevance for tumor biology. Therefore, we independently analyzed their differential regulation in multiple tumors and found severe deregulation in liver, breast, lung, ovarian and kidney cancers, thus proving our GBA hypothesis. Overexpression of KIF18B and CDCA3 in hepatoma cells and subsequent microarray analysis revealed significant deregulation of central cell cycle regulatory genes. Consistently, RT-PCR and proliferation assay confirmed the role of both genes in cell cycle progression.Finally, the prognostic significance of the identified KIF18B- and CDCA3-dependent predictors (P = 0.01, P = 0.04) was demonstrated in three independent HCC cohorts and several other tumors.In summary, we proved the efficacy of large-scale guilt-by-profiling/association strategies in oncology. We identified two novel oncogenes and functionally characterized them. The strong prognostic importance of downstream predictors for HCC and many other tumors indicates the clinical relevance of our findings.