BRCA1/2 Serves as a Biomarker for Poor Prognosis in Breast Carcinoma

Abstract

BRCA1/2 are breast cancer susceptibility genes that are involved in DNA repair and transcriptional control. They are dysregulated in breast cancer, making them attractive therapeutic targets. Here, we performed a systematic multiomics analysis to expound BRCA1/2 functions as prognostic biomarkers in breast cancer. First, using different web-based bioinformatics platforms (Oncomine, TIMER 2.0, UALCAN, and cBioportal), the expression of BRCA1/2 was assessed. Then, the R package was used to analyze the diagnostic value of BRCA1/2 in patients. Next, we determined the relationship between BRCA1/2 mRNA expression and prognosis in patients (PrognoScan Database, R2: Kaplan Meier Scanner and Kaplan−Meier Plotter). Subsequently, the association of BRCA1/2 with mutation frequency alteration and copy number alterations in breast cancer was investigated using the cBioportal platform. After that, we identified known and predicted structural genes and proteins essential for BRCA1/2 functions using GeneMania and STRING db. Finally, GO and KEGG pathway enrichment analyses were performed to elucidate the potential biological functions of the co-expression genes of BRCA1/2. The BRCA1/2 mRNA level in breast cancer tissues was considerably higher than in normal tissues, with AUCs of 0.766 and 0.829, respectively. Overexpression of BRCA1/2 was significantly related to the worse overall survival (p < 0.001) and was correlated to clinicopathological characteristics including lymph nodes, estrogen receptors, and progesterone receptors (p < 0.01). The alteration frequencies of both the gens have been checked, and the results show that BRCA1 and BRCA2 show different alteration frequencies. Their mutation sites differ from each other. GO and KEGG showed that BRCA1/2 was mainly enriched in catalytic activity, acting on DNA, chromosomal region, organelle fission, cell cycle, etc. The 20 most frequently changed genes were closely related to BRCA1/2, including PALB2 and RAD51 relatively. Our study provides suggestive evidence of the prognostic role of BRCA1/2 in breast cancer and the therapeutic target for breast cancer. Furthermore, BRCA1/2 may influence BRCA prognosis through catalytic activity, acting on DNA, chromosomal regions, organelle fission, and the cell cycle. Nevertheless, further validation is warranted.

Keywords: BRCA1/2; breast cancer; multiomics; prognostic biomarkers.

Figure 1

Expression of BRCA1/2 mRNA in cancer vs. normal (Oncomine and TCGA database). (a) This graphic generated by Oncomine (https://www.oncomine.org/resource/login.html, accessed on 10 February 2022) indicates the numbers of datasets with statistically significant (p < 0.01) mRNA overexpression (red) or downexpression (blue) of BRCA1/2 (different types of cancer vs. corresponding normal tissue). The threshold was designed with the following parameters: p value of 1 × 10⁻⁴, fold change of 2, and gene ranking of 10%. (b) Human BRCA1/2 expression levels in different tumor types from TCGA database were determined by TIMER 2.0 (http://timer.cistrome.org, accessed on 10 February 2022) (* p < 0.05; *** p < 0.001).

Figure 2

Expression of BRCA1/2 in BRCA patients. (a) Expression of BRCA1/2 in BRCA based on sample types by UALCAN (http://ualcan.path.uab.edu/index.html, accessed on 10 February 2022). (b) Expression of BRCA1/2 in BRCA by cBioPortal database (https://www.cbioportal.org, accessed on 10 February 2022) (breast invasive carcinoma (TCGA, Cell 2015)).

Figure 3

The diagnostic value of BRCA1/2 in BRCA patients. The diagnostic value of BRCA1/2 in BRCA patients. AUC: area under curve.

Figure 4

Relationship between BRCA1/2 mRNA expression and clinical outcomes in breast cancer patients (PrognoScan Database, R2: Kaplan Meier Scanner and Kaplan–Meier Plotter). (a,b,e,f) The survival curve comparing the patient with high (red), and low (blue) expression of BRCA1/2 was plotted from the PrognoScan database (http://dna00.bio.kyutech.ac.jp/PrognoScan/, accessed on 10 February 2022) in breast cancer patients. The threshold of cox p value < 0.05. (c,g) The survival curve comparing the patient with high (red) and low (blue) expression of BRCA1/2 was plotted from R2: Kaplan Meier Scanner (https://hgserver1.amc.nl/cgi-bin/r2/main.cgi, accessed on 10 February 2022) in TCGA breast cancer patients. The threshold of cox p value < 0.05. (d,h) The survival curve comparing the patient with high (red) and low (black) expression of BRCA1/2 was plotted from Kaplan–Meier Plotter (https://kmplot.com/analysis/, accessed on 10 February 2022) in breast cancer patients. The threshold of cox p value < 0.05.

Figure 5

BRCA1/2 alteration frequency of mutations and copy number alterations (CNAs) in Breast Cancer (cBioPortal web). (a) The alteration frequency of the BRCA1/2 signature was determined cBioPortal (http://www.cbioportal.org, accessed on 10 February 2022). The alteration frequency included mutations (green), amplifications (red), deep deletions (blue), and multiple alterations (grey). (b) Summary of mutations in BRCA1/2 in BRCA from TCGA, cell 2015.

Figure 6

Co-expressed genes of BRCA1/2. (a,b) The top 10 genes with positive and negative co-expression of BRCA1/2 in the TCGA database according to heat map and Venn map. (c) Intersection co-expression genes of BRCA1/2. Note: |r| > 0.4 and p < 0.001.

Figure 7

GO analysis of BRCA1, BRCA2 co-expression genes, and intersection co-expression genes among BRCA1/2. (a) GO analysis of BRCA1, (b) GO analysis of BRCA2, (c) GO analysis of co-expression genes, and intersection co-expression genes among BRCA1/2. GO: Gene Ontology.

Figure 8

KEGG pathway enrichment analysis of BRCA1, BRCA2 co-expression genes, and intersection co-expression genes among BRCA1/2. KEGG pathway enrichment analysis of BRCA1 (a), BRCA2 (b) co-expression genes, and intersection co-expression genes among BRCA1/2 (c). KEGG: Kyoto Encyclopedia of Genes and Genome.

Figure 9

Identification of BRCA1/2 interacting genes and proteins. (a,b) The gene–gene interaction network of BRCA1/2 was constructed using GeneMania. (c,d) The protein–protein interaction network of BRCA1/2 was generated using STRING db.