Mismatch repair deficiency in canine neoplasms
Mismatch repair deficiency in canine neoplasms
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DOI：
10.1177/03009858211022704
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发表时间：
2021-09-19
影响因子：
2.4
通讯作者：
Mizuno, Takuya
中科院分区：
文献类型：
--
作者：
Inanaga, Sakuya;Igase, Masaya;Mizuno, Takuya
DNA错配修复（MMR）系统通过识别和修复DNA复制过程中的错配核苷酸来保持基因组稳定性。MMR系统的功能障碍，也称为错配修复缺陷（dMMR），被认为是免疫检查点阻断疗法疗效的预测性生物标志物，无论人类肿瘤类型如何。本研究旨在评价犬肿瘤中MMR蛋白的免疫标记，并鉴定具有dMMR的肿瘤类型。首先，我们在8种不同的犬肿瘤（口腔恶性黑色素瘤、高至中级淋巴瘤、肥大细胞瘤、恶性乳腺肿瘤、尿路上皮癌、肝细胞癌、骨肉瘤和血管肉瘤）中进行免疫组织化学，各15个样本，以使用抗人单克隆抗体分析犬错配修复蛋白（MSH2、MSH6和MLH1）的免疫标记。我们发现，超过一半的犬口腔恶性黑色素瘤（60%）和肝细胞癌（53%）样本以及较少的其他犬肿瘤在>= 1 MMR蛋白中缺失免疫标记（即，基于人类dMMR的定义，存在缺陷MMR蛋白的证据）。抗人MSH2、MSH6和MLH1的抗体与相应的犬蛋白交叉反应，如使用MMR基因敲除犬细胞系所证实的。需要进一步的研究来调查犬自发性肿瘤与dMMR的临床结果，以确定免疫检查点阻断治疗这些肿瘤类型的潜力。
The DNA mismatch repair (MMR) system preserves genomic stability by identifying and repairing mismatched nucleotides in the DNA replication process. The dysfunction of the MMR system, also known as mismatch repair deficiency (dMMR), is implicated as a predictive biomarker for the efficacy of immune checkpoint blockade therapy regardless of the tumor type in humans. This study aimed to evaluate the immunolabeling of MMR proteins in canine tumors and to identify the types of tumors having dMMR. First, we performed immunohistochemistry in 8 different canine tumors (oral malignant melanoma, high-to-intermediate grade lymphoma, mast cell tumor, malignant mammary gland tumor, urothelial carcinoma, hepatocellular carcinoma, osteosarcoma, and hemangiosarcoma) with 15 samples each to analyze the immunolabeling of canine mismatch repair proteins (MSH2, MSH6, and MLH1) using anti-human monoclonal antibodies. We found that more than half of canine oral malignant melanoma (60%) and hepatocellular carcinoma (53%) samples and fewer of the other canine tumors had loss of immunolabeling in >= 1 MMR protein (ie, evidence of defective MMR proteins, based on the definition of dMMR in the humans). Antibodies against human MSH2, MSH6, and MLH1 were cross-reactive with the corresponding canine protein as confirmed using MMR gene knockout canine cell lines. Further studies are required to investigate the clinical outcomes in canine spontaneous tumors with dMMR to determine the potential for immune checkpoint blockade therapy for these tumor types.