Abstract
Activating mutations of the BRAF gene lead to constitutive activation of the MAPK pathway. The characterization and discovery of BRAF mutations in a variety of human cancers has led to the development of specific inhibitors targeting the BRAF/MAPK pathway and dramatically changed clinical outcomes in BRAF-mutant melanoma patients. Recent discovery of BRAF mutation in canine cancers underscores the importance of MAPK pathway activation as an oncogenic molecular alteration evolutionarily conserved between species. A comparative approach using the domestic dog as a spontaneous cancer model will provide new insights into the dysregulation of BRAF/MAPK pathway in carcinogenesis and facilitate in vivo studies to evaluate therapeutic strategies targeting this pathway’s molecules for cancer therapy. The BRAF mutation in canine cancers may also represent a molecular marker and therapeutic target in veterinary oncology. This review article summarizes the current knowledge on BRAF mutations in human and canine cancers and discusses the potential applications of this abnormality in veterinary oncology.
Highlights
Activating mutations of the BRAF gene lead to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway
Activation of RAF leads to subsequent activation of MEK, initiating the signal transduction of many genes involved in different cellular processes [1] (Figure 1)
This absence of BRAF mutations in canine hematopoietic cancers may reflect the fact that dogs do not develop diseases that are the counterpart of human Langerhans cell histiocytosis (LCH)
Summary
Perhaps the most well described BRAF-mutated cancer in humans is melanoma. Melanoma is a cancer originating in melanocytes, occurring mainly in skin (>90%), and in other locations including eye and mucosal regions [13,14]. The presence of BRAF mutations is associated with UV exposure, and tumors on mucosal sites or non-UV-exposed skin rarely possess the mutation [24,25]. The furred-skin of dogs provides natural protection from UV damage This protection from UV may make dogs less susceptible to UV-related melanoma, resulting in differences in the anatomical location of melanoma between species; the cutaneous form accounts only for ~25% of canine melanoma, with the majority of tumors arising in the oral cavity [21]. 82% of nevi in humans and in 17% of canine melanocytomas [11,26], suggesting the BRAF mutation and consequent MAPK activation may play an important role in the initiation of melanocytic neoplasms, but may be insufficient to cause malignant melanoma without additional molecular alterations
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