Interest of circulating tumor DNA as a biomarker for canine cancers: illustration in histiocytic sarcoma, oral malignant melanoma and multicentric lymphoma

Circulating tumor DNA (ctDNA) has become an attractive biomarker to monitor human cancer patients, with many clinical applications. In the same time, there is a growing interest in integrating natural canine tumors to explore new therapies. The first aim is to show that ctDNA is detectable by targeting different somatic alterations in the plasma of dogs bearing cancers, focusing on histiocytic sarcoma (HS), oral malignant melanoma (OMM) and multicentric lymphoma. The second aim is to illustrate some potential applications in veterinary medicine or in oncology research for diagnosis and monitoring of minimal residual disease (MRD). We found that tumor-specific point mutations, copy number alterations and chromosomal rearrangements were detectable in the plasma of cancer-bearing dogs by ddPCR or PARR methods, allowing the identification of ctDNA in 2/8 (25%) OMM cases, 12/13 (92.3%) lymphoma cases and 21/23 (91.3%) HS cases. The value of a ctDNA test targeting the recurrent PTPN11 mutation to diagnose HS was explored in 133 dogs including 49 with HS, 19 healthy, 14 with non-cancerous diseases, and 51 with other cancers. In this cohort, screening PTPN11 mutations in plasma had a specificity of 98.8% for HS diagnosis, and a sensitivity between 42.8-77% according to HS clinical presentation, being higher in internal forms, especially with pulmonary location. Regarding lymphoma-affected dogs, we explored the value of ctDNA for MRD follow-up by targeting lymphoma-specific antigen receptor rearrangement in the plasma. MRD detection was concordant with the clinical evaluation and ctDNA analysis appeared highly sensitive to assess treatment response and to predict relapse. This study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up in veterinary oncology.