Research Update CHF 02317 Final: The Role of Complex Translocations Associated with TP53 Somatic Mutations for Aiding Prognosis of Canine Diffuse Large B-Cell Lymphoma

This study involved the evaluation of canine lymphoma biopsy specimens for the presence of tumor-associated abnormalities associated with four key cancer-associated genes (MYC, BCL6, BCL2, and TP53). In a subset of human lymphoma patients, cancer cells show structural rearrangements of MYC, BCL2, and/or BCL6, meaning that the normal organization of the gene has become disrupted in the tumor. Human lymphomas also frequently show DNA sequence mutations in the TP53 tumor suppressor gene. The presence of these abnormalities, alone and particular in combination, has been shown to be predictive of a poor response to standard treatment modalities in human lymphoma patients, and provides powerful opportunities to predict prognosis in newly diagnosed patients.

We hypothesized that the same may apply in dogs. We tested this hypothesis using a cohort of canine lymphoma cases that were all treated using standard of care chemotherapy protocols, for which the disease-free interval (DFI) and outcome is known. The aims of the study were to establish a) whether canine lymphomas exhibit abnormalities in these genes and b) to assess whether the presence of one or more of these abnormalities in a tumor specimen is associated with the clinical course of the disease for that case.

We screened the cohort of canine lymphoma cases for structural and numerical abnormalities involving MYC, BCL6, and BCL2. Overall the data suggest that rearrangement of the genome at the MYC and BCL6 loci is relatively rare within any given case. The frequency of MYC rearrangement in dog lymphomas (19% of cases) was similar to that seen in human cases (10-15%), while BCL6 rearrangements were less commonly observed in dog versus human cases (18% and 30%, respectively, Li et al. 2018). Furthermore, 50% of dog cases showed an increase in the number of copies of the MYC gene in tumor cells, compared to normal controls.

In contrast, while BCL2 rearrangements are found in 20-30% of human lymphomas, this abnormality was detected in only 2% of dog tumors. Interestingly, however, dog cases harboring this rearrangement were among the poorest responders to chemotherapy, with a DFI of 38-42 days, compared to a mean of 250 days across the cohort. Furthermore, one case with BCL2 rearrangement was the only case found to also exhibit rearrangements of both MYC and BCL6. In human lymphomas, this combination of events is termed a ‘triple hit’, and is associated with a particularly poor prognosis.

FINAL Research Update Dr. Breen at mutation and response to therapy in lymphoma .