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. 2022 Oct 26;17(10):e0274546.
doi: 10.1371/journal.pone.0274546. eCollection 2022.

An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

Xin Zhou  1 , Guixiang Yao  2 , Jin Zhang  3 , Jiasheng Bian  4 , Guanghao Li  4 , Jianfeng Xu  1
Affiliations

An integrated multi-omics analysis of topoisomerase family in pan-cancer: Friend or foe?

Xin Zhou et al. PLoS One. .

Abstract

Background: Topoisomerases are nuclear enzymes that get to the bottom of topological troubles related with DNA all through a range of genetic procedures. More and more studies have shown that topoisomerase-mediated DNA cleavage plays crucial roles in tumor cell death and carcinogenesis. There is however still a lack of comprehensive multi-omics studies related to topoisomerase family genes from a pan-cancer perspective.

Methods: In this study, a multiomics pan-cancer analysis of topoisomerase family genes was conducted by integrating over 10,000 multi-dimensional cancer genomic data across 33 cancer types from The Cancer Genome Atlas (TCGA), 481 small molecule drug response data from cancer therapeutics response portal (CTRP) as well as normal tissue data from Genotype-Tissue Expression (GTEx). Finally, overall activity-level analyses of topoisomerase in pan-cancers were performed by gene set variation analysis (GSVA), together with differential expression, clinical relevancy, immune cell infiltration and regulation of cancer-related pathways.

Results: Dysregulated gene expression of topoisomerase family were related to genomic changes and abnormal epigenetic modifications. The expression levels of topoisomerase family genes could significantly impact cancer progression, intratumoral heterogeneity, alterations in the immunological condition and regulation of the cancer marker-related pathways, which in turn caused the differences in potential drugs sensitivity and the distinct prognosis of patients.

Conclusion: It was anticipated that topoisomerase family genes would become novel prognostic biomarkers for cancer patients and provide new insights for the diagnosis and treatment of tumors.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. mRNA expression and survival analysis of topoisomerase family genes.
(A) mRNA expression of topoisomerase family genes in the GTEx normal tissues. (B) Differential mRNA expression of topoisomerase family genes in paired tumor and paraneoplastic tissues. The bubble was filtered by the fold change (FC>2) and significance (FDR ≤0.05). (C) Differential expression of topoisomerase family genes associated with cancer subtypes. The black outline border of bubble indicates FDR≤0.05. (D) The trend of the gene expression of topoisomerase family genes from stage I to stage IV in different cancers. The blue trend line and red trend line represent fall and rise tendency, respectively. (E) Survival analysis of topoisomerase family genes in different types of cancer.
Fig 2
Fig 2. Methylation analysis of topoisomerase family genes.
(A) Differential methylation status of topoisomerase family genes in paraneoplastic and tumor tissues in different cancer types. The bubble size is positively correlated with the FDR significance, and the bubble was filtered by FDR significance (FDR ≤0.05). (B) Relationship between methylation level and mRNA expression. (C) Analysis of methylation survival of topoisomerase family genes in different cancers. (D) Survival curves between hypermethylation and hypomethylation groups of TOP1MT in KIRC and HNSC.
Fig 3
Fig 3. SNV analysis of topoisomerase family genes.
(A) The waterfall diagram showed the SNV frequency distribution of topoisomerase family genes in different types of tumors. Side barplot and top barplot show the number of variants in each gene and each sample, respectively. (B) Percentage heatmap showed the topoisomerase family genes SNV frequency in different types of cancer. Each unit of the number represents the number of samples in certain types of cancer mutations. The 0 and blank in the cell indicate there is no mutation in specific gene coding region and all regions of a specific gene, respectively. (C) Lollipop diagrams of TOP2A mutation sites, types and frequencies in UCEC. (D) Lollipop diagrams of TOP2A mutation sites, types and frequencies in SKCM. (E) Survival curve between WT and Mutant groups of TOP1MT in UCEC. (F) Survival curve between WT and Mutant groups of TOP2A in LUAD.
Fig 4
Fig 4. CNV analysis of topoisomerase family genes.
(A) CNV pie chart showed the composition of heterozygous / homozygous CNV of topoisomerase family genes in different cancer types. (B) The heterozygous CNV diagram showed the percentage of heterozygous amplification (red bubbles) and deletions (blue bubbles) of topoisomerase family genes in different types of cancer. The bubble size positively correlated with percentage. (C) Correlation between CNV level and gene expression of topoisomerase family in different types of cancer. (D) Scatter diagram showed the relationship between TOP3A CNV and its mRNA expression in PAAD. (E) CNV survival analysis of topoisomerase family genes in different types of cancer. (F) Kaplan-Meier curve showing the survival difference between different CNV types and wild type of TOP3A in PAAD.
Fig 5
Fig 5. The miRNA regulation network of topoisomerase family genes.
The association between miRNAs and genes suggests that miRNAs have regulatory effects on genes. The size of the node and the degree of the node are positively correlated, and the width of the line is determined by the absolute value of the correlation coefficient.
Fig 6
Fig 6. Pathway activity analysis of topoisomerase family genes.
(A) Gene-pathway network showed the regulatory relationship between topoisomerase family genes and tumor pathways in pan-cancer. (B) Heatmap showing the percentage of cancer types in which specific topoisomerase family genes have an effect on specific pathways (FDR ≤ 0.05) in pan-cancer.
Fig 7
Fig 7. Immune subtype and drug sensitivity analysis of topoisomerase family genes.
(A) Differential expression of topoisomerase family genes in six pan-cancer immune subtypes. (B) Bubble diagram of the relationship between drug sensitivity (IC50) and gene expression level of topoisomerase family genes in CTRP database. Positive correlation (red bubble) indicates one gene with high expression was resistant to a drug, while negative correlation (blue bubble) indicates one gene with high expression was sensitive to a drug. The color depth and size of bubble are positively correlated with the correlation coefficient and the FDR significance, respectively. Black outline border indicates FDR≤0.05.
Fig 8
Fig 8. GSVA analysis of topoisomerase family genes.
(A) Differences of topoisomerase score in paraneoplastic and tumor tissues. The topoisomerase score represents the integrated level of the expression of topoisomerase family genes, which is positively correlated with gene expression. (B) Trend of topoisomerase scores from stage I to stage IV tumors. The blue trend line represents a decreasing score and the red trend line represents an increasing score. (C) Differences in topoisomerase scores among different cancer subtypes. (D) Survival analysis of topoisomerase score in different cancer types, including OS, PFS, DSS, and DFI. (E) Correlation heatmap between topoisomerase score and immune cell infiltration in different cancer types. *: P value≤0.05; #: FDR≤0.05. (F) Correlation heatmap between topoisomerase score and pathway activity in different cancer types. *: P value≤0.05; #: FDR≤0.05.
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