CDK12 is a potential biomarker for diagnosis, prognosis and immunomodulation in pan-cancer

Abstract

Cell cycle-dependent protein kinase 12 (CDK12) plays a key role in a variety of carcinogenesis processes and represents a promising therapeutic target for cancer treatment. However, to date, there have been no systematic studies addressing its diagnostic, prognostic and immunological value across cancers. Here, we found that CDK12 was significantly upregulated in various types of cancers, and it expression increased with progression in ten cancer types, including breast cancer, cholangiocarcinoma and colon adenocarcinoma. Moreover, the ROC curves indicated that CDK12 showed diagnostic value in eight cancer types. High CDK12 expression was associated with poor prognosis in eight types of cancer, including low-grade glioma, mesothelioma, melanoma and pancreatic cancer. Furthermore, we conducted immunoassays to explore the exact mechanisms underlying CDK12-induced carcinogenesis, which revealed that increased expression of CDK12 allowed tumours to evade immune surveillance and upregulate immune checkpoint genes. Additionally, mutational studies have shown that amplification and missense mutations are the predominant mutational events affecting CDK12 across cancers. These findings establish CDK12 as a significant biological indicator of cancer diagnosis, prognosis, and immunotherapeutic targeting. Early surveillance and employment of CDK12 inhibitors, along with concomitant immunotherapy interventions, may enhance the clinical outcomes of cancer patients.

Keywords: CDK12; Diagnosis; Gene mutation; Immunization; Pan-cancer; Prognosis.

Figure 1

Differential expression of CDK12. (A) Expression of CDK12 in normal tissues. (B) Expression of CDK12 in cancer cell lines. (C) Expression of CDK12 in 33 types of cancer. (D) Comparison of CDK12 expression between tumor and normal samples. *p < 0.05, **p < 0.01, ***p < 0.001.nsnot statistically significant.

Figure 2

The protein expression of CDK12 in immunohistochemical images. Normal tissue (left) and tumor tissue (right).

Figure 3

The protein expression level of CDK12 in cancers from CPTAC samples. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 4

Association between CDK12 expression and tumor stage. *p < 0.05, **p < 0.01, ***p < 0.001. nsnot statistically significant.

Figure 5

AUC of ROC curves verified the diagnosis performance of CDK12 in the TCGA cohort.

Figure 6

Association between CDK12 expression and overall survival (OS). (A) Forest plot of OS associations in 33 types of tumor. (B–J) Kaplan–Meier analysis of the association between CDK12 expression and OS.

Figure 7

Association between CDK12 expression and progression-free survival (PFS). (A) Forest plot of PFS associations in 33 types of tumor. (B–G) Kaplan–Meier analysis of the association between CDK12 expression and PFS.

Figure 8

Association between CDK12 expression and disease-specific survival (DSS). (A) Forest plot of DSS associations in 33 types of tumor. (B–H) Kaplan–Meier analysis of the association between CDK12 expression and DSS.

Figure 9

The CDK12 expression correlated with immune infiltration. (A) The CDK12 expression significantly correlated with the infiltration levels of various immune cells in the TIMER database. (B) The CDK12 expression significantly correlated with the infiltration levels of various immune cells based on CIBERSOR. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 10

Correlation analyses of the CDK12 expression with immune checkpoint genes. *p < 0.05, **p < 0.01.

Figure 11

Spearman correlation analysis between the CDK12 gene expression and TMB and MSI. (A) A stick chart shows the relationship between the CDK12 gene expression and TMB in diverse tumors. The red curve represents the correlation coefficient, and the blue value represents the range. (B) A stick chart shows the association between the CDK12 gene expression and MSI in diverse tumors. (C) Relationship between the CDK12 gene expression and TMB or MSI in pan-cancer. Correlation analysis was performed using Spearman’s method.

Figure 12

DNA methylation and mutation features of CDK12 in pan-cancer. (A) Promoter methylation level of CDK12 in pan-cancer. (B) Alteration frequency of CDK12. (C) OncoPrint visual summary of alterations in a query of CDK12 from cBioPortal. (D) The mutation types, number, and sites of the CDK12 genetic alterations. (E) The alteration types of CDK12 in pan-cancer. (F) The related genes alteration frequency in CDK12 altered group and unaltered group.

Figure 13

The gene–gene interaction network of CDK12 from GeneMANIA.