Journal
BLOOD
Volume 125, Issue 6, Pages 999-1005Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-10-602714
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Funding
- Discovery Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) [R-RGPIN-435398]
- Genome Canada [5125]
- BC Cancer Foundation
- Canadian Institutes of Health Research Canada Graduate Scholarship (Master's) award
- NSERC Undergraduate Student Research Award
- Canadian Institutes of Health Research New Investigator award
- Career Investigator award from the Michael Smith Foundation for Health Research
- Terry Fox Program [1023]
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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)-kappa B, 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 TRAF3 mutation. The majority of mutations are predicted to cause loss of TRAF3 protein including those impacting reading frame and splicing. To determine whether TRAF3 loss might be relevant to human NHL, we also analyzed 148 human diffuse large B-cell lymphoma (DLBCL) tumors and identified loss of TRAF3 as a common event, affecting similar to 9% of DLBCLs, and reduced expression of TRAF3 among deleted cases. This study implicates mutations affecting NF-kappa Bactivity as a novel genetic commonality between human and canine NHLs and supports the potential utility of cBCLs with mutated TRAF3 as a model of the more aggressive activated B-cell subgroup of DLBCL.
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