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Research Article
Shengchun Liu
First Affiliated Hospital of Chongqing Medical University
Corresponding Author
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Background: Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). However, there is still a great gap in the study of ferroptosis-related genes in BRCA, especially luminal-type BRCA patients.
Methods: We downloaded the mRNA expression profiles and corresponding clinical data of BRCA patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) databases. Then, we built a prognostic multigene signature with ferroptosis-related differentially expressed genes (DEGs) in the METABRIC cohort and validated it in the TCGA cohort. The predictive value of this signature was investigated in terms of mutations, copy number variations (CNVs), the immune microenvironment and the probability of a response to immunotherapy and chemotherapy.
Findings: The patients were divided into a high-risk group and a low-risk group by the ferroptosis-associated gene signature, and the high-risk group had a worse overall survival (OS). The risk score based on the 10 ferroptosis-related gene-based signature was determined to be an independent prognostic predictor in both the METABRIC and TCGA cohorts (HR, 1.41, 95% CI, 1.14-1.76, P = 0.002; HR, 2.19, 95% CI, 1.13-4.26, P= 0.02). Gene set enrichment analysis indicated that the term “cytokine-cytokine receptor interaction” was enriched in the high-risk score subgroup. Moreover, the immune infiltration scores of most immune cells were significantly different between the two groups, and the low-risk group was much more sensitive to immunotherapy and six drugs might have potential therapeutic implications in high- risk group. In addition, we found that amplifications on chromosome 11 accompanied by the deletion of chromosome 1 were enriched in the high-risk subgroup. Finally, a nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established. This nomogram showed a favorable discriminating ability and might contribute to clinical decision-making for luminal-type breast carcinoma.
Keywords
Ferroptosis, breast cancer, regulated cell death, luminal-type breast carcinoma
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No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
Figure S1. Prognostic analysis of the 10 ferroptosis-related gene signature model in the TCGA cohort. a. The distribution and median value of the risk score in the TCGA cohort. b. The distributions of OS status, OS and risk score in the TCGA cohort. c. Kaplan-Meier curves for the OS of patients in the high-risk group and low-risk group in the TCGA cohort. d. The AUCs of time-dependent ROC curves verified the prognostic performance of the risk score in the TCGA cohort. e. PCA plot of the TCGA cohort. f. t-SNE analysis of the TCGA cohort.
- FigureS2.tif
Figure S2. Functional annotation of genes differentially expressed between the low- and high-risk groups in the TCGA validation cohort. a. Volcano plot of differentially expressed genes between the low- and high-risk groups. Blue indicates the 10 ferroptosis-related genes signature. b. Enrichment plots from gene set enrichment analysis (GSEA) in the TCGA cohort. c. The most significant or shared GO enrichment terms in the TCGA cohort. d. The most significant or shared KEGG pathways in the TCGA cohort.
- TableS1thecompletelistofferroptosisrelatedgenes.pdf
Table S1: The complete list of ferroptosis-related genes
- TableS2thecoefficientsofeachnormalizedexpressionlevelofferroptosisrelatedgenes.pdf
Table S2: The coefficients of each normalized expression level of ferroptosis-related genes
- TableS3Completelistof10candidategeneintheMETABRICcohort.pdf
Table S3: Complete list of 10 candidate gene in the METABRIC cohort
- TableS4Completelistof10candidategeneintheTCGAcohort.pdf
Table S4: Complete list of 10 candidate gene in the TCGA cohort
- TableS5ClinicalrelateddatawithferroptosisrelatedriskscoreinMETABRICcohort.pdf
Table S5: Clinical-related data with ferroptosis-related riskscore in METABRIC cohort
- TableS6ClinicalrelateddatawithferroptosisrelatedriskscoreinTCGAcohort.pdf
Table S6: Clinical-related data with ferroptosis-related riskscore in TCGA cohort
- TableS7immuneinfiltrationscoreintheTCGAcohort.pdf
Table S7: Immune infiltration score in the TCGA cohort
- TableS8Thecorrelationbetweenriskscoreandpathwayscore.pdf
Table S8: The correlation between risk score and pathway score
- TableS9gisticscoresdataofhighrisksubgroup.pdf
Table S9: Gistic scores data of high risk subgroup
- TableS10gisticscoresdataoflowrisksubgroup1.pdf
Table S10: Gistic scores data of low risk subgroup
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Shengchun Liu
First Affiliated Hospital of Chongqing Medical University
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 2
Posted 29 Mar, 2021
No community comments so far
Editorial decision: Major revision
On 12 Jul, 2021
Reviews received
Received 10 Jul, 2021
Reviewers agreed
On 10 Jun, 2021
Reviews received
Received 12 May, 2021
Reviewers agreed
On 02 May, 2021
Reviewers agreed
On 29 Apr, 2021
Reviewers invited
Invitations sent on 28 Apr, 2021
Editor assigned
On 27 Apr, 2021
Editor invited
On 24 Mar, 2021
Submission checks complete
On 24 Mar, 2021
First submitted
On 22 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Ferroptosis is a new form of regulated cell death (RCD), and its emergence has provided a new approach to the progression and drug resistance of breast cancer (BRCA). However, there is still a great gap in the study of ferroptosis-related genes in BRCA, especially luminal-type BRCA patients.
Methods: We downloaded the mRNA expression profiles and corresponding clinical data of BRCA patients from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) databases. Then, we built a prognostic multigene signature with ferroptosis-related differentially expressed genes (DEGs) in the METABRIC cohort and validated it in the TCGA cohort. The predictive value of this signature was investigated in terms of mutations, copy number variations (CNVs), the immune microenvironment and the probability of a response to immunotherapy and chemotherapy.
Findings: The patients were divided into a high-risk group and a low-risk group by the ferroptosis-associated gene signature, and the high-risk group had a worse overall survival (OS). The risk score based on the 10 ferroptosis-related gene-based signature was determined to be an independent prognostic predictor in both the METABRIC and TCGA cohorts (HR, 1.41, 95% CI, 1.14-1.76, P = 0.002; HR, 2.19, 95% CI, 1.13-4.26, P= 0.02). Gene set enrichment analysis indicated that the term “cytokine-cytokine receptor interaction” was enriched in the high-risk score subgroup. Moreover, the immune infiltration scores of most immune cells were significantly different between the two groups, and the low-risk group was much more sensitive to immunotherapy and six drugs might have potential therapeutic implications in high- risk group. In addition, we found that amplifications on chromosome 11 accompanied by the deletion of chromosome 1 were enriched in the high-risk subgroup. Finally, a nomogram incorporating a classifier based on the 10 ferroptosis-related genes, tumor stage, age and histologic grade was established. This nomogram showed a favorable discriminating ability and might contribute to clinical decision-making for luminal-type breast carcinoma.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
No competing interests reported.
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.tif
Figure S1. Prognostic analysis of the 10 ferroptosis-related gene signature model in the TCGA cohort. a. The distribution and median value of the risk score in the TCGA cohort. b. The distributions of OS status, OS and risk score in the TCGA cohort. c. Kaplan-Meier curves for the OS of patients in the high-risk group and low-risk group in the TCGA cohort. d. The AUCs of time-dependent ROC curves verified the prognostic performance of the risk score in the TCGA cohort. e. PCA plot of the TCGA cohort. f. t-SNE analysis of the TCGA cohort.
- FigureS2.tif
Figure S2. Functional annotation of genes differentially expressed between the low- and high-risk groups in the TCGA validation cohort. a. Volcano plot of differentially expressed genes between the low- and high-risk groups. Blue indicates the 10 ferroptosis-related genes signature. b. Enrichment plots from gene set enrichment analysis (GSEA) in the TCGA cohort. c. The most significant or shared GO enrichment terms in the TCGA cohort. d. The most significant or shared KEGG pathways in the TCGA cohort.
- TableS1thecompletelistofferroptosisrelatedgenes.pdf
Table S1: The complete list of ferroptosis-related genes
- TableS2thecoefficientsofeachnormalizedexpressionlevelofferroptosisrelatedgenes.pdf
Table S2: The coefficients of each normalized expression level of ferroptosis-related genes
- TableS3Completelistof10candidategeneintheMETABRICcohort.pdf
Table S3: Complete list of 10 candidate gene in the METABRIC cohort
- TableS4Completelistof10candidategeneintheTCGAcohort.pdf
Table S4: Complete list of 10 candidate gene in the TCGA cohort
- TableS5ClinicalrelateddatawithferroptosisrelatedriskscoreinMETABRICcohort.pdf
Table S5: Clinical-related data with ferroptosis-related riskscore in METABRIC cohort
- TableS6ClinicalrelateddatawithferroptosisrelatedriskscoreinTCGAcohort.pdf
Table S6: Clinical-related data with ferroptosis-related riskscore in TCGA cohort
- TableS7immuneinfiltrationscoreintheTCGAcohort.pdf
Table S7: Immune infiltration score in the TCGA cohort
- TableS8Thecorrelationbetweenriskscoreandpathwayscore.pdf
Table S8: The correlation between risk score and pathway score
- TableS9gisticscoresdataofhighrisksubgroup.pdf
Table S9: Gistic scores data of high risk subgroup
- TableS10gisticscoresdataoflowrisksubgroup1.pdf
Table S10: Gistic scores data of low risk subgroup
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