Genome-Wide Association Study of Golden Retrievers Identifies Germ-Line Risk Factors Predisposing to Mast Cell Tumours

Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.

犬肥大细胞瘤（Canine mast cell tumours, CMCT）是犬类最常见的皮肤肿瘤之一，对犬健康具有重大影响。部分犬种罹患肥大细胞瘤的风险更高，提示潜在的易感种系遗传因素在该疾病的发生发展中发挥作用。目前该疾病的遗传风险因素在很大程度上仍未明确，尽管已有研究在部分CMCT病例中检测到癌基因C-KIT的体细胞突变，这使得CMCT可作为C-KIT突变频发的人类肥大细胞增多症的比较模型。本研究对来自两大洲的金毛寻回犬开展了全基因组关联研究（Genome Wide Association Study），并在两个种群中分别鉴定出与CMCT发病风险相关的基因组区域。对关联区域进行序列捕获，并在更大规模的犬队列中开展后续精细定位后，研究人员在GNAI2基因中鉴定出与CMCT发病相关的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）（P值为2.2×10^-16），该变异可导致该基因产生可变剪接形式，进而形成截短蛋白。此外，研究分别在欧洲和美国金毛寻回犬中鉴定出两类携带透明质酸酶基因的疾病相关单倍型：犬20号染色体（cfa20）上的HYAL1、HYAL2与HYAL3基因，以及犬14号染色体（cfa14）上的HYAL4、SPAM1与HYALP1基因，上述结果提示透明质酸的代谢周转在CMCT的发生发展中扮演重要角色。