Abstract
Background
Breast cancer is the most common cancer and the leading cause of death among women. KRAS is known as an oncogene, its expression also associates with cancer prognosis. The purpose of this study was to investigate the prognostic value of KRAS expression in breast cancer and its relationship with immune infiltration.
Methods
Firstly, the expression level and methylation of KRAS were analyzed. Then survival analysis was used to verify the prognostic capability of KRAS expression. After that, gene functional enrichment analysis was performed. The relationship between KRAS gene expression and immune infiltration was researched later.
Results
The expression level of KRAS in breast cancer was increased (P = 2.2e−16). Tumor KRAS expression in the subtypes of basal-like, HER2-enriched, Luminal A and Luminal B were 1.64, 1.67, 1.51 and 1.42 times of normal, respectively. 13 methylation sites were different between tumor and normal tissues and associated with KRAS expression. Subsequently, Kaplan–Meier analysis suggested that the high KRAS expression group had a poor prognosis (P = 0.0028). In multivariate Cox regression analysis, KRAS expression was an independent prognostic indicator (HR = 1.353, 95% CI 1.009–1.814, P = 0.044). Gene Ontology (GO) analysis showed enrichment of epidermal growth associated pathways. Additionally, different KRAS expression levels represented different tumor immune infiltration status, which may be caused by the influence of the RAS/MAPK and RAS/PI3K pathways on the level of PD-L1.
Conclusion
This study suggests that KRAS expression can be used as a prognostic indicator of breast cancer, and it is closely related to tumor immune infiltration.
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Data availability
The gene expression data is available in UCSC Xena (https://xenabrowser.net) and the methylation data can download from MEXPRESS database (https://mexpress.be/index.html). The validation Kaplan–Meier diagram was drawn on Kaplan–Meier Plotter (https://kmplot.com/analysis/). The molecular correlation data is available in TIMER database (https://cistrome.shinyapps.io/timer/). The statistical analysis used an open source software R 3.6.1 (https://www.r-project.org/).
Abbreviations
- GO:
-
Gene Ontology
- TNBC:
-
Triple-negative breast cancer
- OS:
-
Overall survival
- ssGSEA:
-
Single-sample gene set enrichment analysis
- HR:
-
Hazard ratio
- CI:
-
Confidence interval
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Acknowledgements
We thank Tianyi Zhou for the Internet technical assistance and the work by Yixin Wang and his (her) colleagues.
Funding
This study was supported in part by Guangxi Medical University Innovation and Entrepreneurship Training Program (Grant no. 201910598261).
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HL, JL, and GZ designed and conceived the study. JP downloaded the data from online databases. HL and JL analyzed the data. GZ and LL wrote the manuscript.
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Supplementary file2 Supplementary Fig. 2 The Kaplan–Meier diagram of OS for breast cancer molecular subtypes (high KRAS expression group vs low KRAS expression group). a Luminal A (133 vs 154); b Luminal B (48 vs 26); c HER2-enriched (17 vs 15); d basal-like (48 vs 38) (JPG 294 kb)
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Supplementary file3 Supplementary Fig. 3 Comparison of immune infiltration in breast cancer molecular subtypes with high- and low-KRAS expression level. a Luminal A; b Luminal B; c HER2-enriched; d basal-like. “*” represents P < 0.05, “**” represents P < 0.01, “***” represents P < 0.001 (JPG 500 kb)
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Supplementary file4 Supplement Table 1 Clinical and pathological characteristics of patients and their tumors in cohort GSE2034 (include training set and validation set) (DOC 50 kb)
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Supplementary file5 Supplementary Table 2 Correlation analysis between KRAS and gene markers of tumor immune infiltrate cells (DOC 70 kb)
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Liang, H., Zhou, G., Lv, L. et al. KRAS expression is a prognostic indicator and associated with immune infiltration in breast cancer. Breast Cancer 28, 379–386 (2021). https://doi.org/10.1007/s12282-020-01170-4
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DOI: https://doi.org/10.1007/s12282-020-01170-4