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. 2022 Jul 10;10(2):156-174.
doi: 10.2478/jtim-2022-0013. eCollection 2022 Jun.

Pan-cancer Landscape of the RUNX Protein Family Reveals their Potential as Carcinogenic Biomarkers and the Mechanisms Underlying their Action

Shen Pan  1 , Siyu Sun  2 , Bitian Liu  3 , Yang Hou  1
Affiliations

Pan-cancer Landscape of the RUNX Protein Family Reveals their Potential as Carcinogenic Biomarkers and the Mechanisms Underlying their Action

Shen Pan et al. J Transl Int Med. .

Abstract

Background: The RUNX family of transcription factors plays an important regulatory role in tumor development. Although the importance of RUNX in certain cancer types is well known, the pan-cancer landscape remains unclear.

Materials and methods: Data from The Cancer Genome Atlas (TCGA) provides a pan-cancer overview of the RUNX genes. Hence, herein, we performed a pan-cancer analysis of abnormal RUNX expression and deciphered the potential regulatory mechanism. Specifically, we used TCGA multi-omics data combined with multiple online tools to analyze transcripts, genetic alterations, DNA methylation, clinical prognoses, miRNA networks, and potential target genes.

Results: RUNX genes are consistently overexpressed in esophageal, gastric, pancreatic, and pan-renal cancers. The total protein expression of RUNX1 in lung adenocarcinoma, kidney renal clear cell carcinoma (KIRC), and uterine corpus endometrial carcinoma (UCEC) is consistent with the mRNA expression results. Moreover, increased phosphorylation on the T14 and T18 residues of RUNX1 may represent potential pathogenic factors. The RUNX genes are significantly associated with survival in pan-renal cancer, brain lower-grade glioma, and uveal melanoma. Meanwhile, various mutations and posttranscriptional changes, including the RUNX1 D96 mutation in invasive breast carcinoma, the co-occurrence of RUNX gene mutations in UCEC, and methylation changes in the RUNX2 promoter in KIRC, may be associated with cancer development. Finally, analysis of epigenetic regulator co-expression, miRNA networks, and target genes revealed the carcinogenicity, abnormal expression, and direct regulation of RUNX genes.

Conclusions: We successfully analyzed the pan-cancer abnormal expression and prognostic value of RUNX genes, thereby providing potential biomarkers for various cancers. Further, mutations revealed via genetic alteration analysis may serve as a basis for personalized patient therapies.

Keywords: RUNX family; The Cancer Genome Atlas; pan-cancer analysis; prognosis; regulatory mechanism.

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Figures

Figure 1
Figure 1
Pan-cancer expression of RUNX genes. (A) Comparison of RUNX mRNA expression in cancer and adjacent normal tissues. (B) Comparison of RUNX expression data from TCGA and GTEx databases in cancers that lacked or had fewer normal tissues. (C) Total RUNX protein expression in certain cancers. (D) The pan-cancer landscape of RUNX expression at mRNA and protein levels. (E) Heatmap of RUNX gene expression in various tissues. *P < 0.05, **P < 0.01, and ***P < 0.001. TCGA: The Cancer Genome Atlas; GTEx: genotype-tissue expression; BLCA: bladder urothelial carcinoma; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: lower-grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; PRAD: prostate adenocarcinoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UVM: uveal melanoma.
Figure 2
Figure 2
Phosphorylation analysis of RUNX proteins in different tumors. (A) Box plots show the phosphorylation sites in RUNX proteins that are positively associated with different cancers. (B) The RUNX protein schematic shows phosphoprotein sites with positive results. *P < 0.05, **P < 0.01, and ***P < 0.001. KIRC: kidney renal clear cell carcinoma; LUAD: lung adenocarcinoma; UCEC: uterine corpus endometrial carcinoma.
Figure 3
Figure 3
RUNX-associated survival analyses. Positive association of (A) RUNX1, (B) RUNX2, and (C) RUNX3 with OS and DFS. (D) The pan-cancer survival landscape of RUNX genes. OS: overall survival; DFS: disease-free survival; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; GBM: glioblastoma multiforme; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LGG: lower-grade glioma; UVM: uveal melanoma; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; GBM: glioblastoma multiforme; KIRC: kidney renal clear cell carcinoma; STAD: stomach adenocarcinoma; BLCA: bladder urothelial carcinoma; KICH: kidney chromophobe; SKCM: skin cutaneous melanoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; HNSC: head and neck squamous cell carcinoma; LAML: acute myeloid leukemia; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; PRAD: prostate adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma.
Figure 4
Figure 4
Pan-cancer genetic alterations in RUNX genes. Bar graphs showing the frequencies of genetic alteration in (A) RUNX1, (B) RUNX2, and (C) RUNX3 genes. Relationship between the genetic alteration and expression of (D) RUNX1 in LAML, ESCA, and UCEC and (E) RUNX2 in ESCA, STAD, and UCEC. *P < 0.05, **P < 0.01, ***P < 0.001. LAML: acute myeloid leukemia; ESCA: esophageal carcinoma; UCEC: uterine corpus endometrial carcinoma; STAD: stomach adenocarcinoma; ns: not significant (P > 0.05); BRCA: breast carcinoma; BLCA: bladder urothelial carcinoma; COAD: colon adenocarcinoma; UVM: uveal melanoma; LUSC: lung squamous cell carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; LUAD: lung adenocarcinoma; HNSC: head and neck squamous cell carcinoma; SKCM: skin cutaneous melanoma; THYM: thymoma; TGCT: testicular germ cell tumors; PRAD: prostate adenocarcinoma; PAAD: pancreatic adenocarcinoma; GBM: glioblastoma multiforme; KIRC: kidney renal clear cell carcinoma; LGG: lower-grade glioma; KIRP: kidney renal papillary cell carcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; KICH: kidney chromophobe; LIHC: liver hepatocellular carcinoma; THCA: thyroid carcinoma; READ: rectum adenocarcinoma; UCS: uterine carcinosarcoma; OV: ovarian serous cystadenocarcinoma; SARC: sarcoma; ACC: adrenocortical carcinoma; PCPG: pheochromocytoma and paraganglioma; CHOL: cholangiocarcinoma; MESO: mesothelioma.
Figure 5
Figure 5
RUNX mutations in cancer. (A) Pan-cancer amino acid mutations in RUNX in TCGA. Hotspot mutations are indicated. (B) Co-occurrence of RUNX mutations. (C) The distribution frequency of mutations in the domains of each RUNX family protein. (D) Correlation between the expression of RUNX genes and TMB. *P < 0.05, **P < 0.01, and ***P < 0.001. TCGA: The Cancer Genome Atlas; TMB: tumor mutation burden; COAD: colon adenocarcinoma; STAD: stomach adenocarcinoma; GBM: glioblastoma multiforme; UCEC: uterine corpus endometrial carcinoma; PAAD: pancreatic adenocarcinoma; SKCM: skin cutaneous melanoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; UVM: uveal melanoma; THYM: thymoma; THCA: thyroid carcinoma; TGCT: testicular germ cell tumors; PRAD: prostate adenocarcinoma; LUSC: lung squamous cell carcinoma; LUAD: lung adenocarcinoma; LIHC: liver hepatocellular carcinoma; LGG: lower-grade glioma; LAML: acute myeloid leukemia; KIRP: kidney renal papillary cell carcinoma; KIRC: kidney renal clear cell carcinoma; KICH: kidney chromophobe; HNSC: head and neck squamous cell carcinoma; GBM: glioblastoma multiforme; ESCA: esophageal carcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; BRCA: breast carcinoma; BLCA: bladder urothelial carcinoma; ACC: adrenocortical carcinoma; UCS: uterine carcinosarcoma; SARC: sarcoma; MESO: mesothelioma; READ: rectum adenocarcinoma; PCPG: pheochromocytoma and paraganglioma; OV: ovarian serous cystadenocarcinoma; CHOL: cholangiocarcinoma.
Figure 6
Figure 6
Pan-cancer fusion gene and methylation analysis of RUNX. (A) Fusion gene analysis of RUNX in cancer. (B) Differential methylation bubble plot showing changes in RUNX methylation between tumor and normal samples for each cancer type. Blue points represent reduced methylation in tumors; red points represent increased methylation in tumors; the deeper the color, the higher the difference; point size represents significance; bigger the point, higher the significance. (C) Pearson correlation between methylation and RUNX mRNA expression. Blue points represent negative correlations; red points represent positive correlations; the deeper the color, the greater the correlation. (D) Survival difference between individuals with hypermethylated and hypomethylated RUNX genes. Only genes with a significant log P-value (≤0.05) are shown in the figure. The red point indicates the high risk of the high-methylation group; the blue point indicates the low risk of the high-methylation group; BRCA: breast carcinoma; COAD: colon adenocarcinoma; HNSC: head and neck squamous cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; KIRC: kidney renal clear cell carcinoma; LIHC: liver hepatocellular carcinoma; THCA: thyroid carcinoma; PAAD: pancreatic adenocarcinoma; ESCA: esophageal carcinoma; BLCA: bladder urothelial carcinoma; PRAD: prostate adenocarcinoma; UCEC: uterine corpus endometrial carcinoma; TGCT: testicular germ cell tumors; SKCM: skin cutaneous melanoma; UVM: uveal melanoma; THYM: thymoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; LGG: lower-grade glioma; KICH: kidney chromophobe; STAD: stomach adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; GBM: glioblastoma multiforme; ACC: adrenocortical carcinoma; UCS: uterine carcinosarcoma; SARC: sarcoma; MESO: mesothelioma; READ: rectum adenocarcinoma; PCPG: pheochromocytoma and paraganglioma; CHOL: cholangiocarcinoma.
Figure 7
Figure 7
Analysis of the methylation probes, cg17064250 and cg09541256, upstream of the RUNX2 TSS in KIRC. Survival analysis and distribution of the methylation level of the RUNX2 probes, (A) cg17064250 and (B) cg09541256, in KIRC. (C) A schematic representing the relationship between the methylation level of all RUNX2 probes and the expression of RUNX2. The red box marked the methylation level in the upstream of RUNX2 TSS. (D) The upstream probes, cg17064250 and cg09541256, of the RUNX2 partial transcript TSS exhibit a significant negative correlation with RUNX2 expression. *P < 0.05, **P < 0.01, and ***P < 0.001. TSS: transcription start site; KIRC: kidney renal clear cell carcinoma.
Figure 8
Figure 8
Co-expression of RUNX genes and epigenetic regulators. *P < 0.05, **P < 0.01, and ***P < 0.001. BLCA: bladder urothelial carcinoma; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: lower-grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; PRAD: prostate adenocarcinoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UVM: uveal melanoma; CHOL: cholangiocarcinoma; MESO: mesothelioma; OV: ovarian serous cystadenocarcinoma; PCPG: pheochromocytoma and paraganglioma; READ: rectum adenocarcinoma; SARC: sarcoma; UCS: uterine carcinosarcoma.
Figure 9
Figure 9
The pan-cancer pathway and miRNA network of RUNX genes. (A) Pathway activity showing the overall influence of RUNX on the tumorigenesis pathway in 32 cancer types ([the number of activated or inhibited cancers/32] × 100%). (B) Heatmap showing RUNX proteins that are functional (inhibited or activated) in at least five cancer types. Pathway_A (red) represents the percentage of cancers whose pathways can be activated by a given gene; pathway_I (blue) represents the percentage of cancers whose pathways can be inhibited by a given gene. (C) Correlation between RUNX genes and immune and stroma infiltration scores. (D) The pan-cancer miRNA network regulating RUNX genes. Edge width is defined by the absolute value of the correlation coefficient. BLCA: bladder urothelial carcinoma; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: lower-grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; PRAD: prostate adenocarcinoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UVM: uveal melanoma; CHOL: cholangiocarcinoma; MESO: mesothelioma; OV: ovarian serous cystadenocarcinoma; PCPG: pheochromocytoma and paraganglioma; READ: rectum adenocarcinoma; SARC: sarcoma; UCS: uterine carcinosarcoma.
Figure 10
Figure 10
The transcriptional regulatory genes of RUNX proteins. (A) Genes appearing in at least three target gene sets are defined as candidate targets of RUNX genes. The white dashed line delineates candidate target genes in the Venn diagram. Pan-cancer heatmap showing the correlation between candidate target genes and (B) RUNX1 and (C) RUNX2. *P < 0.05, **P < 0.01, and ***P < 0.001. BLCA: bladder urothelial carcinoma; BRCA: breast carcinoma; CESC: cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck squamous cell carcinoma; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: lower-grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; PAAD: pancreatic adenocarcinoma; PRAD: prostate adenocarcinoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UVM: uveal melanoma.
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