Genetic causes of canine mast cell tumours (MCTs), except for mutations in the KIT gene detected in some MCTs, are generally unknown. We used whole exome sequencing to reveal mutation spectra in canine MCTs. We detected somatic mutations in 87 genes including 10 genes recognized as human cancer drivers. Besides KIT, 14 other genes were recurrently mutated. Subsequently, we performed next generation sequencing of a panel of 50 selected genes in additional MCT samples. In this group, the most frequently altered gene was GNB1 showing a recurrent dinucleotide substitution at position of Gly116 in 30% of the MCT samples (n = 6/20) and Ile80 substitution accompanied by a splice region mutation in one case. We extended the study by analysis of the above mentioned GNB1 regions in additional MCT samples by Sanger sequencing, and assessed the overall prevalence of GNB1 mutations to 17.3% (n = 14/81), which is similar to the prevalence of KIT alterations. Our results indicate that GNB1 mutations are probably involved in canine MCT pathogenesis in both cutaneous and subcutaneous MCT cases. As opposed to KIT alterations, the presence of GNB1 mutations did not negatively affect survival times, and our data even showed a trend towards positive prognosis. If our results are confirmed in a larger number of MCTs, an extension of molecular testing of canine MCTs by GNB1 analysis would help to refine the molecular stratification of MCTs, and become useful for targeted treatment strategies.

中文翻译：

---

通过下一代测序在犬肥大细胞肿瘤中检测到复发性基因突变。

除了在某些 MCT 中检测到的KIT基因突变外，犬肥大细胞瘤 (MCT) 的遗传原因通常是未知的。我们使用全外显子组测序来揭示犬 MCT 中的突变谱。我们在 87 个基因中检测到体细胞突变，其中包括 10 个被认为是人类癌症驱动因素的基因。除了KIT之外，还有 14 个其他基因反复发生突变。随后，我们对其他 MCT 样本中的一组 50 个选定基因进行了下一代测序。在该组中，最常改变的基因是GNB1，在 30% 的 MCT 样本（n = 6/20）中，在 Gly116 的位置显示出重复的二核苷酸取代，在一个案例中，Ile80 取代伴有剪接区突变。我们通过分析上述内容扩展了研究通过 Sanger 测序在其他 MCT 样本中的GNB1区域，并评估GNB1突变的总体流行率为17.3% (n = 14/81)，这与KIT改变的流行率相似。我们的结果表明，在皮肤和皮下 MCT 病例中，GNB1 突变可能与犬 MCT 发病机制有关。与 KIT 改变相反，GNB1突变的存在不会对生存时间产生负面影响，我们的数据甚至显示出积极预后的趋势。如果我们的结果在更多的 MCT 中得到证实，那么通过GNB1分析扩展犬 MCT 的分子检测将有助于完善 MCT 的分子分层，并对靶向治疗策略有用。