Genetic inactivation of TRAF3in canine and human B-cell lymphoma

Non-Hodgkin lymphomas (NHLs) are the most common cancer to affect pet dogs. In contrast to the many genes whose mutation contributes to lymphomagenesis in humans, relatively little is known about the acquired genetic alterations that lead to canine B-cell lymphomas (cBCLs). We performed a survey of 84 canine NHL tumors to identify genes affected by somatic point mutations. We found mutations affecting TRAF3,which encodes a negative regulator of nuclear factor (NF)-κB, to be a common feature of cBCLs, with mutations observed in 44’ of tumors including a combination of somatic and rare germ-line variants. Overall, 30’ of the tumors contained ≥1 somatic TRAF3mutation. The majority of mutations are predicted to cause loss of TRAF3protein including those impacting reading frame and splicing. To determine whether TRAF3loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3as a common event, affecting ∼9’ of DLBCLs, and reduced expression of TRAF3among deleted cases. This study implicates mutations affecting NF-κB activity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3as a model of the more aggressive activated B-cell subgroup of DLBCL.