Heterozygous amplification and deletion associates in dysregulation of the CDK family genes in cancers
RNA sequencing data from the TCGA database were used to analyze the expression levels of CDK family genes in a wide range of cancers. The results showed that most of the CDK family genes, such as CDK1, CDK5, CDK4, CDK2, CDK16, CDK7, CDK6, CDK12, CDK8, CDK17, and CDK13, were up-regulated across various cancer types. In contrast, we also observed that CDK14, CDK15, and CDK20 were down-regulated in some cancer types, and CDK9, CDK11A, and CDK11B remained unchanged (Fig. 1A). To further understand the cause of the core CDK family genes is transcriptionally dysregulated, we studied the CNV in a pan-cancer. The results showed that CDK family genes heterozygous amplification and heterozygous deletion were dominant. CNV analysis of heterozygous amplification and deletion displayed that CDK family genes had the highest amplification due to heterozygosity in KIRP, and have the highest frequency of loss of heterozygosity in KICH (Fig. 1B). However, the frequencies of homozygous amplification and deletion were very low (Fig. 1C). These above findings suggested that heterozygous amplification and deletion were most likely to result in the transcriptional dysregulation of CDK family genes.
Furthermore, we analyzed the effects of CDK family gene expression on survival risk, which showed that CDK2 and CDK1 survival worse than other genes in KIRC, KIRP, and KICH (Figure S1A). In BLCA, BRCA, KIRC, and STAD, mRNA expression levels of CDK family genes were also shown in Figure S1B. Additionally, gene expression analysis of the CDK family genes in the GTEx dataset revealed that CDK9 has the highest expression value in most normal tissues, such as fallopian tube, nerve, ovary, pituitary, spleen, and uterus, followed by CDK4 and CDK16 (Figure S1C).
Methylated Cdk Family Genes In Cancers
DNA methylation is an important mechanism involved in aberrant gene expression and carcinogenesis (13). Therefore, we further performed the methylation analysis in various cancer types. CDK6 has the highest increase in methylation rate in BRCA, followed by CDK17 in UCEC and BLCA, and CDK9 in LIHC. The methylation levels of CDK16, CDK1, CDK11B, CDK10, and CDK5 were significantly decreased (Fig. 2A). Previous reports have revealed that the methylation levels may be associated with the regulation of gene expression in cancer tissues (14). Therefore, we applied the correlation analysis between expression and methylation levels of CDK family genes in various cancer types. The results showed that CDK6, CDK9, CDK4, and CDK18 genes with increased methylation levels, and CDK16 and CDK10 genes with decreased methylation levels were negatively correlated with gene expression in some cancer types (Fig. 2B). We also studied the patients’ overall survival difference between hypermethylation and hypomethylation, indicating that CDK2, CDK15, CDK10, CDK17, CDK12, CDK11B, and CDK11A survival worse than other CDK members in several cancer types (Figure S3).
Frequency Analysis Of Cdk Family Genes Mutation In Cancers
Firstly, we detected the mutation profile in various cancer types and found that most of the CDK family genes were frequently mutated. CDK12 and CDK13 have the highest mutation frequency in UCEC, STAD, BLCA, and COAD (Fig. 3A). An integrated analysis of the mutation types of CDK family genes exhibited that SNPs were dominant (Figure S4A). Missense mutations occur most frequently (Figure S4B). In addition, the mutation has the highest frequency of C > T conversion (Figure S4C). The median variation of each tumor sample was 1 (Figure S4D). For each mutation type, missense mutation has the highest number of mutations per capita (Figure S4E). The high-frequency mutation CDK family genes were CDK12, CDK13, CDK11B, CDK14, CDK11A, CDK15, CDK19, CDK18, CDK16, and CDK17, respectively (Figure S4F). Moreover, among the variances in the CDK family genes, CDK12 had the highest mutation frequency (28%), followed by CDK13 (18%), and CDK11B (10%) (Fig. 3B).
In addition, CNV pie distribution displayed that heterozygous amplification and heterozygous deletion of CDK family genes were dominant (Figure S2A). We further explored the analysis of the Pearson correlation between CNV and mRNA expression and found that the expression levels of almost all CDK family genes were significantly associated with CNV in BRCA. Among them, CDK12 was the most relevant (Figure S2B).
Pathway Analysis Of Cdk Family Genes
To further explore the biological functions of these CDK family genes, we performed the correlation pathway analysis. The results showed that CDK activation or inhibition could influence apoptosis, cell cycle, DNA damage response, EMT, PI3K/AKT, RAS/MAPK, RTK, and TSC/mTOR pathways (Figure S5). In these pathways, activation of CDK6, CDK4, CDK2, and CDK1 could activate apoptosis and cell cycle, and inhibit RAS/MAPK. CDK17, CDK15, and CDK14 activation could activate EMT and suppress cell cycle. Besides, activation of CDK16 could activate the cell cycle, and CDK7 could inhibit RAS/MAPK, RTK, and TSC/mTOR pathways (Fig. 4).
Drug Sensitivity Analysis Of Cdk Family Genes
We detected the drug sensitivity analysis of CDK family genes. The results showed that BX-912, PIK-93, XMD13-2, and KIN001-236 were strongly negatively associated with CDK13 expression (Fig. 5). Z-LLNle-CHO was negatively correlated with CDK6. PLX4720 was negatively associated with CDK2. Moreover, NPK76-Ⅱ-72-1 was negatively related to CDK11A. PIK-93 was negatively associated with CDK14. Furthermore, Trametinib was positively associated with CDK19 and CDK1. TGX221 was positively correlated with CDK8. Navitoclax was positively associated with CDK7. In addition, Methotrexate presented the most significant positive correlation with CDK16 expression and had a significant negative correlation with CDK9 and CDK11B (Fig. 5). These above candidate small molecule drugs could reverse the expression of CDK family genes, thus providing novel directions and molecular mechanisms for treating cancers.