Somatic Structural And Numerical Aberrations In Bovine Leukemia Virus Induced Tumors

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 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. To examine gross numerical and structural variants (SVs) we assayed 12 bovine tumors on the BovineSNP50 Illumina BeadChip as well as 22 ovine tumors on the OvineSNP50 Illumina BeadChip. We also carried out whole genome sequencing (~30X) on 4 ovine tumors with matched normal tissue. Initial examination of the tumors revealed frequent aneuploidy, with orthologous regions of the genome involved in both species. Focal SVs identified included an amplification (>4 copies) of the terminus of BTA16 in three tumors (contains PTPRC & miR-181), while the tumor suppressor CDKN2A on OAR2 was deleted in multiple ovine tumors. For the 4 sequenced tumors multiple time points over the course of infection were available allowing us to determine when these SVs arose via nested PCR. Interestingly we observed that the SVs involving well know cancer driver genes generally appear many months prior to tumor development. These preliminary results indicate that tumors induced by HTLV-1 and BLV display somatic structural changes that impinge on overlapping sets of genes and point to the emergence of SVs affecting cancer driver genes in the preleukemic clone, well before the clone undergoes rapid expansion