Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets

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.

Identification of differentially expressed HERV-K(HML-2) loci in colorectal cancer

“…Detecting HERV-K in blood as a non-invasive molecular marker could provide a rapid and effective method for tumor screening and assessment ( Dervan et al, 2021 ). Upregulation of HERV-K mRNA and encoded protein expression has been frequently reported in various cancers recently ( Shah et al, 2022 ; Wei et al, 2022 ; Yang et al, 2022 ). Although its role in oncogenic mechanisms is still unidentified, it is clear that abnormal HERV-K expression can be used as a diagnostic and therapeutic target for cancer ( Zhang et al, 2019 ).…”

“…The preferential expression of HERV-K gag 22q11.23 in prostate cancer tissues and the observed increase in advanced prostate cancer made this protein a potential biomarker for detecting prostate cancer progression and recurrence rates ( Reis et al, 2013 ). The expression profiles of 91 known HERV-K proviruses could be used as biomarkers to distinguish breast cancer from healthy individuals ( Wei et al, 2022 ). For example, HERV-K(HML-2) 17p13.1 provirus was strongly associated with breast cancer risk ( Wei et al, 2022 ).…”

“…The expression profiles of 91 known HERV-K proviruses could be used as biomarkers to distinguish breast cancer from healthy individuals ( Wei et al, 2022 ). For example, HERV-K(HML-2) 17p13.1 provirus was strongly associated with breast cancer risk ( Wei et al, 2022 ). Analyzing differentially expressed HERV in RNA-seq data from TCGA-COAD, results showed that upregulated genes enriched pathways related to epigenetic gene regulation.…”

Alternative and aberrant splicing of human endogenous retroviruses in cancer. What about head and neck? —A mini review

“…An oncogenic role for HERV-K has been proposed. In fact, HERV-K transcripts and proteins have been detected in several cancer types, including teratocarcinoma ( 50 – 55 ), trophoblastic tumors and germ cell tumors ( 56 , 57 ), seminomas ( 58 – 60 ), breast cancer ( 61 – 67 ), prostate cancer ( 68 – 71 ), leukemias ( 72 – 77 ), renal cancer ( 78 ), ovarian cancer ( 79 – 81 ), cervical cancer ( 28 , 82 ), melanoma ( 83 – 87 ), soft tissue sarcoma ( 88 ), osteosarcoma ( 89 ), Kaposi’s sarcoma ( 90 ), glioblastoma ( 91 ), astrocytic tumors ( 92 ), hepatoblastoma ( 93 , 94 ), and hepatocellular carcinoma ( 95 ).…”

Transcriptome Analysis of Human Endogenous Retroviruses at Locus-Specific Resolution in Non-Small Cell Lung Cancer

“…Recently, human endogenous retroviruses (HERVs), a class of transposable elements, have been found to be implicated in cancer development and later employed as novel diagnostic, prognostic, and treatment response biomarkers for several tumor types [ 10 , 11 , 12 , 13 , 14 , 15 ]. In more detail, HERVs are remnants of exogenous retroviruses integrated into the human genome during evolution, accounting for 8% of the human genome.…”