Analysis of the Expression of Repetitive DNA Elements in Osteosarcoma

Abstract

Osteosarcoma (OS) is a rare malignant bone tumor. It affects mostly young persons and has poor outcome with the present treatment. No improvement was observed since the introduction of chemotherapy. The better understanding of osteosarcoma development could indicate better management strategy. Repetitive DNA elements were found to play a role in cancer mechanism especially in epithelial tumors but not yet analyzed in osteosarcoma. We conducted the study to analyse the expression profile of repetitive elements (RE) in osteosarcoma.Methods: Fresh bone paired (tumor and normal bone) samples were obtained from excised parts of tumors of 18 patients with osteosarcoma. We performed sequencing of RNA extracted from 36 samples (18 tumor tissues and 18 normal bone for controls), mapped raw reads to the human genome and identified the REs. EdgeR package was used to analyse the difference in expression of REs between osteosarcoma and normal bone.Results: 82 REs were found differentially expressed (FDR < 0.05) between osteosarcoma and normal bone. Out of all significantly changed REs, 35 were upregulated and 47 were downregulated. HERVs (THE1C-int, LTR5, MER57F and MER87B) and satellite elements (HSATII, ALR-alpha) were the most significantly differential expressed elements between osteosarcoma and normal tissues. These results suggest significant impact of REs in the osteosarcoma. The role of REs should be further studied to understand the mechanism they have in the genesis of osteosarcoma.

Peer Review #2 of "Biomarker potential of repetitive-element transcriptome in lung cancer (v0.2)"

“…osteosarcoma (Ho et al, 2017), and may support the potential capability of REs not only as diagnostic biomarkers, but also as prognostic biomarkers for specific diseases, as reported in other studies (Ahn et al, 2013;Kabanov and Tishchenko, 2015). Since (i) RE expression seems to depend on read-through transcription (Gnanakkan et al, 2013;Deininger et al, 2017), (ii) RE expression change no longer seems to be related with class, type or even family ( Fig.…”

“…osteosarcoma (Ho et al, 2017). A possible explanation may be that HERV elements (and, by extension, HERV-derived REs) are subject to strong epigenetic controls that keep them essentially silent, except in cancer, autoimmunity and placental development (Hurst and Magiorkinis, 2017).…”

ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses

“…Many ERVs are expressed during embryogenesis and are subsequently epigenetically silenced (7). However, certain ERV sequences are actively transcribed and are elevated in diseases, including various cancers, multiple sclerosis, amyotrophic lateral sclerosis, and HIV-1 infection (8–15). Most ERV sequences have acquired numerous mutations over time and therefore do not have protein-coding potential or the potential to generate infectious viral particles.…”

HSATII RNA is induced via a non-canonical ATM-regulated DNA-damage response pathway and facilitates tumor cell proliferation and movement

“…Overexpression of HSATII RNA has been reported for lung, ovarian, prostate and osteosarcoma tumors as well as tumor-derived cell lines (10,12,13). Given our current data revealing the importance of the DDR in HSATII RNA expression and with the known impact of deregulated DDRs and cell cycle checkpoints on oncogenesis (91, 92), we probed the physiological consequences of HSATII RNA expression in cultured tumor cells.…”

“…Several ncRNAs originating from satDNA regions of the genome are expressed in cancer cells, such as human alpha-satellite repeat (Alpha/ALR) RNA, human satellite II (HSATII) RNA and its mouse counterpart GSAT RNA (10)(11)(12)(13). While some satDNA transcription is stress-dependent (14) or triggered during apoptotic, differentiation or senescence programs in cells (15,16), HSATII RNA accumulation was found to be refractory to these generalized stressors.…”