Abstract
ObjectiveHuman endogenous retroviruses (HERVs) make up 8% of the human genome. HERVs are biologically active elements related to multiple diseases. HERV-K, a subfamily of HERVs, has been associated with certain types of cancer and suggested as an immunologic target in some tumors. The expression levels of HERV-K in breast cancer (BCa) have been studied as biomarkers and immunologic therapeutic targets. However, HERV-K has multiple copies in the human genome, and few studies determined the transcriptional profile of HERV-K copies across the human genome for BCa.MethodsNinety-one HERV-K indexes with entire proviral sequences were used as the reference database. Nine raw sequencing datasets with 243 BCa and 137 control samples were mapped to this database by Salmon software. The differential proviral expression across several groups was analyzed by DESeq2 software.ResultsFirst, the clustering of each dataset demonstrated that these 91 HERV-K proviruses could well cluster the BCa and control samples when the normal controls were normal cells or healthy donor tissues. Second, several common HERV-K proviruses that are closely related with BCa risk were significantly differentially expressed (padj < 0.05 and absolute log2FC > 1.5) in the tissues and cell lines. Additionally, almost all the HERV-K proviruses had higher expression in BCa tissue than in healthy donor tissue. Notably, we first found the expression of 17p13.1 provirus that located with TP53 should regulate TP53 expression in ER+ and HER2+ BCa.ConclusionThe expression profiling of these 91 HERV-K proviruses can be used as biomarkers to distinguish individuals with BCa and healthy controls. Some proviruses, especially 17p13.1, were strongly associated with BCa risk. The results suggest that HERV-K expression profiles may be appropriate biomarkers and targets for BCa.
Highlights
Breast cancer (BCa) is the most common cancer diagnosed in women and is one of the three most common cancers worldwide [1, 2].The heterogeneity, complex etiology, diverse gene mutations, and different clinical manifestations of BCa denote that all kinds of internal and external risk factors may participate in BCa pathogenesis
All raw sequencing data and clinic information downloaded from the Gene Expression Omnibus and National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) were mapped to the 91 human endogenous retrovirus (HERV)-K provirus indexes by Salmon software
DEseq2 was used to compare the digital expression between BCas and controls in the eight datasets separately to obtain the differentially expressed HERV-Ks in each dataset
Summary
Breast cancer (BCa) is the most common cancer diagnosed in women and is one of the three most common cancers worldwide [1, 2].The heterogeneity, complex etiology, diverse gene mutations, and different clinical manifestations of BCa denote that all kinds of internal and external risk factors may participate in BCa pathogenesis. Previous studies have shown that human endogenous retrovirus (HERV) can stimulate tumor cell proliferation and avoid apoptosis, which is one of the most important factors for tumor progression [6]. Most HERVs have become dysfunctional because of the accumulation of multiple nonsense mutations, and some are still active and may play a role in human disease. 90 HERV-K proviruses and many smaller elements have been detected in the human genome [14]. HERV-K has multiple copies in the human genome, and some complete open reading frames can be found in HERVK proviruses. HERV-Ks often demonstrate important roles on BCa, studies on the transcriptional activity of this provirus across the human genome are still lacking
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