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

Abstract

Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology and may be informative in cancer-affected dogs. By performing ddPCR or PARR methods, we detected tumor-specific point mutations, copy number alterations and chromosomal rearrangements in the plasma of cancer-affected dogs. It allowed the detection of ctDNA in 2/8 (25%) oral malignant melanoma cases, 12/13 (92.3%) lymphoma cases and 21/23 (91.3%) histiocytic sarcoma (HS) cases. The value of ctDNA to diagnose HS was explored in 133 dogs including 49 with HS. In this cohort, screening recurrent PTPN11 mutations in plasma had a specificity of 98.8%, and a sensitivity between 42.8-77% according to HS clinical presentation, being higher in internal forms, especially with pulmonary location. Regarding lymphoma, the follow-up of four dogs showed that the minimal residual disease detection by targeting lymphoma-specific antigen receptor rearrangement in the plasma was concordant with the clinical evaluation. Moreover, ctDNA analysis appeared interesting 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 relevant biomarker for diagnosis and clinical follow-up. With a growing interest in integrating natural canine tumors to explore new therapies, this biomarker appears promising in comparative oncology research.

Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Dogs With Tumors

“…The molecular basis of the relationship between tumor burden and cfDNA levels was identified in this study. Moreover, an increase in cfDNA levels was observed 42 days before clinical relapse (e.g., an increase in lymph node size), confirming the potential of cfDNA measurements for monitoring tumor relapse ( 18 ). However, in our study, dogs no.…”

“…A significant discovery of our study is the correlation between the sum of LD and the cfDNA level of dogs with multicentric lymphoma; thus, continual monitoring of plasma cfDNA concentrations might be useful to assess the response to chemotherapy in patients with multicentric lymphoma. A recent study confirmed the correlation between cfDNA fraction (% of total plasma cfDNA) obtained through PCR for antigen receptor rearrangement ( 18 ) and the sum of LD during chemotherapy in four dogs with high-grade B -cell multicentric lymphoma. The molecular basis of the relationship between tumor burden and cfDNA levels was identified in this study.…”

“…In veterinary medicine, not many studies have been reported yet, but several studies have demonstrated the potential role of cfDNA in non-invasive early diagnosis. Some of these studies have focused on quantifying cfDNA levels to distinguish benign from malignant diseases ( 9 , 17 , 18 ). In the present study, plasma cfDNA concentrations were used to distinguish between clinically ill dogs and healthy dogs.…”

Horizons in Veterinary Precision Oncology: Fundamentals of Cancer Genomics and Applications of Liquid Biopsy for the Detection, Characterization, and Management of Cancer in Dogs

“…Published research on canine cfDNA has covered a variety of clinical applications, including trauma, sepsis, thromboembolism, and neoplasia, and has focused primarily on determining the concentration of cfDNA in plasma as correlated to a particular clinical state or as a predictor for certain clinical outcomes ( 84 , 148 – 151 , 167 , 169 , 191 – 203 ). Studies that evaluated cfDNA concentrations in healthy canine subjects have reported median concentrations ranging from less than 1 ng/mL to greater than 500 ng/mL ( 148 , 149 , 167 , 169 , 194 – 203 )—significantly wider than the range documented in healthy humans (typically 0–20 ng/mL) ( 204 ). These wide-ranging findings suggest that additional research employing well-controlled, large-scale studies is required to better understand the fundamental characteristics of cfDNA in dogs; they also point to the need for standardized, reproducible methods for blood collection, extraction, and measurement of canine cfDNA.…”