Cook Shawna R, Hugen Sanne, Hayward Jessica J, Famula Thomas R, Belanger Janelle M, McNiel Elizabeth, Fieten Hille, Oberbauer Anita M, Leegwater Peter A J, Ostrander Elaine A, Mandigers Paul J J, Evans Jacquelyn M
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2416723122. doi: 10.1073/pnas.2416723122. Epub 2025 May 30.
Gastric cancer ranks as the fifth most common human cancer worldwide and has a poor survival rate and limited treatment options. Despite the high prevalence and mortality rate, the genetic etiology is largely unknown. In dogs, a clinically and histologically similar disease disproportionately affects two breeds, the Belgian Tervuren and Belgian Sheepdog, which develop the intestinal and diffuse tumor subtypes observed in humans. We performed a Bayesian genome-wide association study and selection analyses in this naturally occurring canine model to elucidate underlying genetic risk factors for gastric cancer and identified 15 associated loci. Variant filtering revealed germline putative regulatory variants for the () and genes and a coding variant in . Two loci are overrepresented among cases of intestinal tumor subtype. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop gastric cancer. Across-breed analyses uncovered haplotypes enriched in Malinois at and that are at significantly higher frequency among genome-wide association study controls. Among Tervuren and Sheepdogs, putative regulatory variants were present at comparatively high frequency and were associated with risk of gastric cancer. Here, we describe a complex genetic architecture governing gastric cancer in a dog model, including genes such as and , that have not been associated with human gastric cancer.
胃癌是全球第五大常见人类癌症，生存率低且治疗选择有限。尽管其发病率和死亡率很高，但其遗传病因在很大程度上仍不清楚。在犬类中，一种临床和组织学上相似的疾病不成比例地影响两个品种，即比利时特弗伦犬和比利时牧羊犬，它们会发展出人类中观察到的肠道和弥漫性肿瘤亚型。我们在这个自然发生的犬类模型中进行了贝叶斯全基因组关联研究和选择分析，以阐明胃癌的潜在遗传风险因素，并确定了15个相关位点。变异筛选揭示了 （） 和 基因的种系推定调控变异以及 中的一个编码变异。两个位点在肠道肿瘤亚型病例中过度代表。尽管与特弗伦犬和牧羊犬密切相关，但比利时马林诺斯犬很少患胃癌。跨品种分析发现，在 和 处马林诺斯犬中富集的单倍型在全基因组关联研究对照中频率显著更高。在特弗伦犬和牧羊犬中，推定的调控变异以相对较高的频率出现，并与胃癌风险相关。在这里，我们描述了一个在犬类模型中控制胃癌的复杂遗传结构，包括 和 等尚未与人类胃癌相关联的基因。
