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Abstract :
[en] 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 about ~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 (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary somatic events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a tumor. At the current time little is known about the landscape of somatic changes in BLV induced tumors and the timing of their occurrence. To address this we have carried out whole genome sequencing of BLV induced tumors from two cattle, and from five sheep with matched normal tissue. This revealed frequent aneuploidy, with orthologous regions of the genome involved in both species and elevated mitochondria DNA copy numbers in tumors. Recurrent structural variants (SVs) were seen affecting the tumor suppressors CDKN2A and ARID1A, both on OAR2. On average ~1400 somatic SNVs were observed in each ovine tumor, with high/moderate impact variants in known cancer drivers genes such as KMT2A, ATRX, RPL22 and KRAS. The five sheep were also sampled at regular time points, prior to leukemia onset, allowing us to examine tumor clone evolution. High throughput 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. Low coverage sequencing of samples prior to tumor development indicates that aneuploidy of OAR9 is a feature of the majority of BLV infected clones. Preliminary nested PCR also showed that many SVs were present prior to tumor development. High throughput approaches are being developed to track both SVs and SNV in the preleukemic stages of the disease.
Event place :
Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom