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- Title
The landscape and evolution of somatic alterations in BLV induced tumors.
- Authors
J., Wayet; K., Durkin; A. S., Reuter; N., Shahzad; A., Leduc; P., Griebel; N., Arsic; A., Facciuolo; A., Burny; C., Charlier
- Abstract
Objectives Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an aggressive leukemia/lymphoma in ~ 5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate. Viral transcripts/proteins and provirus integration within the host genome play a critical role in cell survival and expansion, however somatic events are likely to be important as only a subset of naturally infected individuals, following many years of asymptomatic infection, develop a tumor. At the current time little is known about the landscape of somatic alterations in BLV-induced tumors and the timing of their occurrence. Methods To address this, we have carried out whole genome sequencing and single-cell RNA-seq of BLV-induced tumors and matched normal tissue. Results WGS revealed copy number variants (CNVs) with aneuploidy of OAR9 observed in all tumors examined. Recurrent structural variants (SVs) were seen affecting important tumor suppressors. On average 2860 somatic SNVs were observed in each tumor, with high-impact variants in known cancer driver genes. Target-seq single-cell NGS approaches were applied to track the transcriptional impact of these alterations. Sheep were also sampled at regular time points, prior to leukemia onset, allowing us to examine tumor clone evolution. Sequencing of proviral integration sites showed that the tumor clone represents only a small fraction of the infected cells for the majority of the disease, only expanding rapidly in the terminal stages. Conclusion We have uncovered somatic alterations in full-blown BLV-induced tumors. Preliminary NGS data obtained from samples prior to tumor development suggest that CNVs and aneuploidy are features of the majority of non-malignant BLV-infected clones. Single-cell approaches are being developed to track both SVs and SNVs in pre-leukemic stages of the disease.
- Publication
AIDS Reviews, 2023, Vol 25, p16
- ISSN
1139-6121
- Publication type
Article