Integrated pancancer analysis reveals the oncogene characteristics and prognostic value of DIP2B in breast cancer

Abstract

BackgroundDisco-interaction protein 2 homologue B (DIP2B) plays an important role in DNA methylation. There have been many reports on DIP2B in various diseases, but neither the diagnostic value nor the prognostic value of DIP2B across cancer types has been deeply explored.MethodsThe expression levels of DIP2B in 33 cancer types were analysed based on data sets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database. The relationships of DIP2B expression with immune cell infiltration and immune-related gene expression were studied via the CIBERSORT, ESTIMATE and TISIDB tools. Gene set variation analysis (GSVA) was performed to identify pathways related to DIP2B. DIP2B knockdown by siRNA was performed in breast cancer cell lines to investigate the effect on proliferation, apoptosis and migration. The relationships of DIP2B expression with clinicopathological features and prognosis were analysed based on immunohistochemistry.ResultsDIP2B was highly expressed in 26 of 33 cancer types and was significantly associated with poor overall survival (OS) in breast invasive carcinoma (BRCA), mesothelioma and chromophobe renal cell carcinoma (each P < 0.05). DIP2B showed a negative correlation with the immune score, the infiltration levels of key immune killer cells (CD8 + T cells, activated NK cells and plasma cells), and the expression of major histocompatibility complex–related genes and chemokine-related genes in BRCA. Subtype analysis showed that DIP2B expression was associated with poor OS in Her-2 + BRCA patients (P < 0.05). DIP2B showed a negative correlation with immune killer cell infiltration and immune regulatory genes in BRCA subtypes. In BRCA, the GSVA results revealed that genes correlating positively with DIP2B were enriched in cancer-related pathways (PI3K-AKT) and cell-cycle-related pathways (MITOTIC_SPINDLE, G2M_CHECKPOINT and E2F_TARGETS), while genes correlating negatively with DIP2B were enriched in DNA_REPAIR. Knockdown of the DIP2B gene induced a reduction in proliferation and migration and an increase in apoptosis in breast cancer cell lines. DIP2B expression was associated with lymph node metastasis and poor histological grade in BRCA according to immunohistochemistry (each P < 0.05). DIP2B expression predicted reduced disease-free survival and OS in BRCA patients (each P < 0.05), especially those with the Her-2 + subtype (P = 0.023 and P = 0.069).ConclusionsDIP2B may be a prognostic biomarker for BRCA, especially for the Her-2 + subtype. DIP2B is associated with a “cold” tumour immune microenvironment in BRCA and might serve as a future target for immunotherapy.