Familial adenomatous polyposis in dogs: hereditary gastrointestinal polyposis in Jack Russell Terriers with germline APC mutations
Familial adenomatous polyposis in dogs: hereditary gastrointestinal polyposis in Jack Russell Terriers with germline APC mutations
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DOI：
10.1093/carcin/bgaa045
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发表时间：
2021-01-01
期刊：
影响因子：
4.7
通讯作者：
Sakai, Hiroki
中科院分区：
文献类型：
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作者：
Yoshizaki, Kyoko;Hirata, Akihiro;Sakai, Hiroki
狗的许多遗传性疾病在人类中也有类似的情况，因此作为天然动物模型而受到关注。某些疾病的品种易感性通常为探索狗的新型遗传性疾病提供了有希望的线索。最近，日本杰克罗素梗犬（JRT）胃肠道（GI）息肉病例有所增加。在 21 例受影响的 JRT 中，在胃和结直肠中的一个或两个中发现了息肉，其中好发于胃窦和直肠。 21 只检查犬中，有 13 只发现多发性息肉，其中 5 只同时患有胃息肉和结直肠息肉。有些狗狗在很小的时候就被发现患有胃肠道息肉，最小的病例只有2.3岁。组织病理学上，46 个胃肠道息肉中有 43 个（93.5%）被诊断为腺瘤或腺癌。免疫组织化学分析显示肿瘤细胞中 fr-catenin 在细胞质和细胞核中积累。与患有家族性腺瘤性息肉病的人类患者一样，所有检查的胃肠道息肉 JRT (n = 21) 都具有相同的杂合种系 APC 突变，以 2 bp 替换为代表 (c.[462A>T, 463A>T])。后一种取代是无义突变 (p.K155X)，导致 APC 蛋白截短，因此表明与这种易患癌症的疾病密切相关。在 JRT 的胃肠道肿瘤中检测到野生型 APC 等位基因的体细胞突变和缺失，表明双等位基因 APC 失活与肿瘤的发展有关。这项研究表明，尽管人类和狗的疾病状况存在差异，但种系 APC 突变导致狗和人类都有患胃肠道肿瘤性息肉的倾向。
Many hereditary disorders in dogs have equivalents in humans and thus attract attention as natural animal models. Breed predisposition to certain diseases often provides promising clues to explore novel hereditary disorders in dogs. Recently, cases of gastrointestinal (GI) polyps in Jack Russell Terriers (JRTs) have increased in Japan. In 21 affected JRTs, polyps were found in either or both the stomach and colorectum, with a predilection for the gastric antrum and rectum. Multiple polyps were found in 13 of 21 examined dogs, including 5 dogs with both gastric and colorectal polyps. Some dogs were found to have GI polyps at an early age, with the youngest case being 2.3 years old. Histopathologically, 43 of 46 GI polyps (93.5%) were diagnosed as adenomas or adenocarcinomas. Immunohistochemical analysis revealed cytoplasmic and nuclear accumulation of fr-catenin in the tumor cells. As in the case of human patients with familial adenomatous polyposis, all examined JRTs with GI polyps (n = 21) harbored the identical heterozygous germline APC mutations, represented by a 2-bp substitution (c.[462A>T, 463A>T]). The latter substitution was a non-sense mutation (p.K155X) resulting in a truncated APC protein, thus suggesting a strong association with this cancer-prone disorder. Somatic mutation and loss of the wild-type APC allele were detected in the GI tumors of JRTs, suggesting that biallelic APC inactivation was involved in tumor development. This study demonstrated that despite differences in the disease conditions between human and dog diseases, germline APC mutation confers a predisposition to GI neoplastic polyps in both dogs and humans.