National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genet. 2013 Mar;9(3):e1003409. doi: 10.1371/journal.pgen.1003409. Epub 2013 Mar 28.
The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P(raw) = 1.60 × 10(-7); P(genome) = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 × 10(-8)). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.
家犬是研究复杂疾病易感性遗传的有力模型。现代品种的培育和繁殖策略导致特定品种特定疾病的风险增加。一个例子是标准贵宾犬（STPOs），它们患有数字鳞状细胞癌（SCCD）的风险增加，这是一种局部侵袭性癌症，导致溶骨性骨病变，有时伴有多个脚趾复发。然而，只有深色皮毛的 STPOs 具有高风险；浅色 STPOs 几乎完全不受影响，这表明多个途径之间的相互作用对于肿瘤发生是必要的。我们对 STPOs 进行了全基因组关联研究（GWAS），将 31 例 SCCD 病例与 34 例无关的黑色 STPO 对照进行了比较。犬 15 号染色体上的峰值 SNP 在全基因组水平上具有统计学意义（P(raw)=1.60×10(-7);P(genome)=0.0066）。进一步的定位解析了该区域到 KIT 配体（KITLG）基因座。将 STPO 病例与其他高危品种进行比较，将该基因座缩小到 144.9-Kb 区域。在 84 例 STPO 病例中进行的单倍型图谱分析确定了一个最小的 28.3 Kb 区域。在 STPOs 中发现了一个与 SCCD 强烈相关的包含预测增强子元件的拷贝数变异（CNV）（P=1.72×10(-8))。浅色 STPOs 携带与黑色 STPOs 相同频率的 CNV 风险等位基因，但不易患 SCCD。将 24 只黑色和 24 只浅色 STPOs 进行 GWAS 比较，仅发现 MC1R 基因座在两个数据集之间存在显著差异，表明 MC1R 基因座内的补偿性突变可能使浅色 STPOs免受疾病影响。我们的研究结果突出了 KITLG 在 SCCD 易感性中的作用，并表明 KITLG 和 MC1R 基因座之间的相互作用可能是 SCCD 肿瘤发生所必需的。这些发现强调了研究仅限于特定品种的疾病如何有助于阐明多基因疾病。
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