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Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer.

ABSTRACT: Patients with the luminal B subtype of breast cancer exhibit a poor prognosis, high metastatic risk and high incidence of chemotherapy resistance. Luminal B breast cancer is sub-classified into B1 and B2. The pathophysiological mechanism of luminal B2 breast cancer (LB2BC) progression has yet to be characterized. Therefore, the present study aimed to identify the genes involved in the pathogenesis of LB2BC. The data of 117 LB2BC expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and differentially expressed genes (DEGs) were identified by comparison with non-tumor tissue expression profiles. Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) networks were used to obtain insight into the functions of DEGs. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was performed to validate the expression level of DEGs in tissue samples. A total of 2,251 DEGs, including 759 upregulated and 1,492 downregulated genes, were identified between LB2BC and non-tumor tissues. The top 15 upregulated and downregulated genes were used to construct a PPI network: Epidermal growth factor receptor (EGFR), fibronectin-1 (FN1) and Polo-like kinase-1 had the highest connectivity degrees. KEGG analysis identified that DEGs were most significantly enriched in 'focal adhesion', 'pathways in cancer' and 'ECM-receptor interaction' pathways. The results of RT-qPCR demonstrated that EGFR was significantly downregulated in LB2BC, whereas FN1 was significantly upregulated, whereas neurotrophic receptor tyrosine kinase 2 (NTRK2) trended towards downregulation. In conclusion, the DEGs identified in the present study, including NTRK2, FN1 and EGFR, may serve pivotal roles in the tumorigenesis of LB2BC by affecting the 'focal adhesion', 'pathways in cancer' and 'ECM-receptor interaction' KEGG pathways.

SUBMITTER: Wang J

PROVIDER: S-EPMC5727610 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer.

Wang Jinguang J Du Qi Q Li Chen C

Oncology letters 20171023 6

Patients with the luminal B subtype of breast cancer exhibit a poor prognosis, high metastatic risk and high incidence of chemotherapy resistance. Luminal B breast cancer is sub-classified into B1 and B2. The pathophysiological mechanism of luminal B2 breast cancer (LB2BC) progression has yet to be characterized. Therefore, the present study aimed to identify the genes involved in the pathogenesis of LB2BC. The data of 117 LB2BC expression profiles were downloaded from The Cancer Genome Atlas (T ...[more]

PMID: 29250180

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Project description:BackgroundHeterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.MethodsWe performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.ResultsBased on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.ConclusionOur findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

Dataset Information

Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer.

Publications

Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer.

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