Structural And Numerical Somatic Changes In BLV Induced Tumors

Background
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 neoplasm. Recent work in HTLV-1 induced adult T cell leukemia/lymphoma (ATL) identified a large number of somatic changes associated with malignancy. At the current time little is known about the landscape of somatic changes in BLV induced tumors.

Methods
To examine gross numerical and structural aberrations in BLV induced tumors we assayed 12 bovine tumors on the BovineSNP50 Illumina BeadChip as well as 22 ovine tumors on the OvineSNP50 Illumina BeadChip. The resultant data was examined with penCNV in combination with visual inspection of the Log R ratios and B allele frequencies.

Results
The tumors from both species showed frequent aneuploidy with the whole or a large part of chromosomes BTA5, BTA10, BTA14 and BTA24 duplicated in >50% of the bovine tumors. In the ovine tumors chromosomes OAR5, OAR7, OAR9 and OAR16 were frequently duplicated. It is interesting to note that BTA14 is orthologous to OAR9 and both are orthologous to HSA8q, a part of the human genome frequently duplicated in ATLs and other leukemias. In addition a number of focal structural variants were observed. In cattle the terminus of BTA16, which includes the CD45 gene and miR-181 was amplified (>4 copies) in three tumors. In sheep, mirroring observations in ATL, the CDKN2A gene was deleted in multiple tumors.

Conclusion
These preliminary results indicate that tumors induced by HTLV-1 and BLV display somatic structural changes that impinge on overlapping sets of genes. Secondarily, it appears that in the case of BLV despite the much shorter incubation periods in sheep, the resultant tumors in both the natural and the experimental host display evidence of substantial genome instability.