Abstract
The high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis. Areas with high DNA methylation (such as CpG islands) were accompanied by copy number variation (CNV), and these genomic variations affected the level of DNA methylation. In this study, we characterized intertumor heterogeneity and analyzed the effects of CNV on DNA methylation and gene expression. In addition, we performed a Genetic Set Enrichment Analysis (GSEA) to identify key pathways for changes between patients with low and high expression of genes. Our analysis found two key genes, namely, HPDL and SOX17. The protein expressed by HPDL is 4-hydroxyphenylpyruvate dioxygenase-like protein, which has dioxygenase activity. SOX17 is a transcription factor that can inhibit Wnt signaling, promote the degradation of activated CTNNB1, and participate in cell proliferation. Our analysis found that the CNV of HPDL and SOX17 is not only related to the patient's prognosis, but also related to gene methylation and expression levels affecting the patient's survival time. Among them, the high-methylation, low-expression HPDL and SOX17 showed poor prognosis. And the addition of two copies of SOX17 is associated with a lower survival rate, while a decrease in the copy number of HPDL also suggests a poor prognosis. This study provided an effective bioinformatics basis for further exploration of molecular mechanisms related to BRCA and assessment of patient prognosis, but the development of biomarkers for diagnosis and treatment still requires further clinical data validation.
Highlights
Rapidly evolving high-throughput sequencing technologies have enabled the acquisition of vast amounts of multiomics data more efficiently [1]. e variation of expression of some genes causes the genetic regulation trajectory inside the cell to deviate, which alters the gene expression programming inside the cell. erefore, most disease-causing genomic variants are likely to play a role by altering gene regulation, such as transcription factor binding and DNA methylation, rather than directly affecting protein function [2, 3]. e high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis [4]
In this study, BRCArelated methylation data downloaded from the e Cancer Genome Atlas Genetic Set Enrichment Analysis (GSEA) (TCGA) database included 883 samples, comprising 96 normal tissue samples and 787 BRCA tissue samples. e difference analysis results obtained a total of 122 proteincoding genes with P < 0.05 and |logFC| > 1 as the cutoff condition (Figure 1(a)). e copy number variation (CNV) data included 2201 samples, 1103 normal tissue samples, and 1098 BRCA tissue samples
As the CNV of HPDL and SOX17 are related to methylation and abnormal expression levels, our research indicated that the CNV of HPDL and SOX17 can directly affect the prognosis of patients and can indirectly affect the survival time of patients by affecting the methylation and expression levels of the corresponding genes
Summary
Rapidly evolving high-throughput sequencing technologies have enabled the acquisition of vast amounts of multiomics data more efficiently [1]. e variation of expression of some genes causes the genetic regulation trajectory inside the cell to deviate, which alters the gene expression programming inside the cell. erefore, most disease-causing genomic variants are likely to play a role by altering gene regulation, such as transcription factor binding and DNA methylation, rather than directly affecting protein function [2, 3]. e high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis [4].In human cancer, genomic instability leads to extensive cell copy number variation (CNV) [5]. Erefore, most disease-causing genomic variants are likely to play a role by altering gene regulation, such as transcription factor binding and DNA methylation, rather than directly affecting protein function [2, 3]. E high heterogeneity of breast cancer (BRCA) makes it more challenging to interpret the genetic variation mechanisms involved in BRCA pathogenesis and prognosis [4]. It has been found that changes in CNV such as BRCA1, BLM, and OR4C11. BRCA1 is a transcriptional activator that can regulate the cell cycle; BLM is involved in DNA replication and repair, and OR4C11 can regulate cell signal transduction [8], while changes in CNV such as MYC and JAK2 play a role in acquired chemotherapy resistance to triple-negative BRCA [9]. The higher intratumoral heterogeneity of EGFR/CEP7 and CCND1/CEP11 CNV could predict metastasis and was significantly correlated with metastasis-free survival in triple negative BRCA patients [10]
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