Biomarker potential of repetitive-element transcriptome in lung cancer

Abstract

Since repetitive elements (REs) account for nearly 53% of the human genome, profiling its transcription after an oncogenic change might help in the search for new biomarkers. Lung cancer was selected as target since it is the most frequent cause of cancer death. A bioinformatic workflow based on well-established bioinformatic tools (such as RepEnrich, RepBase, SAMTools, edgeR and DESeq2) has been developed to identify differentially expressed RNAs from REs. It was trained and tested with public RNA-seq data from matched sequencing of tumour and healthy lung tissues from the same patient to reveal differential expression within the RE transcriptome. Healthy lung tissues express a specific set of REs whose expression, after an oncogenic process, is strictly and specifically changed. Discrete sets of differentially expressed REs were found for lung adenocarcinoma, for small-cell lung cancer, and for both cancers. Differential expression affects more HERV-than LINE-derived REs and seems biased towards down-regulation in cancer cells. REs behaving consistently in all patients were tested in a different patient cohort to validate the proposed biomarkers. Down-regulation of AluYg6 and LTR18B was confirmed as potential lung cancer biomarkers, while up-regulation of HERVK11D-Int is specific for lung adenocarcinoma and up-regulation of UCON88 is specific for small cell lung cancer. Hence, the study of RE transcriptome might be considered another research target in cancer, making REs a promising source of lung cancer biomarkers.

HERV-K(HML7) Integrations in the Human Genome: Comprehensive Characterization and Comparative Analysis in Non-Human Primates

“…Contrarily, HML7 and HML8 elements still remain poorly characterized. In particular, the only data regarding HML7 elements come from a recent study investigating the overall differential expression of repetitive elements in the transcriptome of patients with lung cancer for biomarker identification purposes [ 26 ]. In the study, participants were divided into patients who developed lung adenocarcinoma (LUAD) and patients who have developed small cell lung cancer (SCLC).…”

“…In the study, participants were divided into patients who developed lung adenocarcinoma (LUAD) and patients who have developed small cell lung cancer (SCLC). The analysis showed a significant upregulation of the inner portion of HML-7 elements (known as HERVK11D-int) specific to LUAD but not found in SCLC patients [ 26 ]. Importantly, the study evaluated the whole group modulation, i.e., without any information about the individual HML7 member expression.…”

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

“…Families with a higher percentage of differentially expressed HERVs included HERV-H, HERV-K, and MER4. Interestingly, up-regulation of the HERV-H and HERV-K families has been proposed as novel diagnostic biomarkers [ 47 , 48 , 49 ], while the up-regulation of the MER4 family has been linked to progression-free survival (PFS) and overall survival (OS) [ 11 ]. MER4 HERVs have also been proposed as novel biomarkers for the response to immune checkpoint inhibitors (ICI), which, currently, are becoming the standard first-line treatment of advanced NSCLC for patients with high PD-L1 expression [ 11 ].…”

Human endogenous retroviruses in viral disease and therapy

“…16 On the other hand, many reports have indicated that HERVs are involved in different types of diseases. For example, HERV dysregulation has been detected in various types of cancer, such as breast cancer (BC), 17,18 melanoma, 19,20 kidney cancer, 21,22 lung cancer, 23,24 and ovarian cancer (OC). 25,26 In addition, HERVs are related to other diseases, such as type 1 diabetes, 27 neurological diseases 28 and other autoimmune diseases.…”