Gain-of-function mutation in PTPN11 in histiocytic sarcomas of Bernese Mountain Dogs
Gain-of-function mutation in PTPN11 in histiocytic sarcomas of Bernese Mountain Dogs
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DOI：
10.1111/vco.12357
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发表时间：
2018-06-01
影响因子：
2.1
通讯作者：
Kiupel, M.
中科院分区：
文献类型：
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作者：
Thaiwong, T.;Sirivisoot, S.;Kiupel, M.
组织细胞肉瘤（HS）是一种树突状细胞来源的侵袭性恶性肿瘤，常见于某些品种的犬。在伯尔尼山地犬（BMDs）中描述了致死性、播散性HS的高患病率。在几项研究中已经提出了遗传易感性发展HS的支持，但迄今为止，尚未报告致病的遗传事件。此外，在肿瘤中没有发现驱动突变。最近，PTPN 11基因编码的SHP 2中的E76 K功能获得性突变已在人类组织细胞恶性肿瘤中被描述。在我们的研究中，我们确定了PTPN 11（E76 K）在骨密度的HS。采用PCR扩增PTPN 11基因第3外显子，然后进行桑格测序的方法，对30只BMDs、13只金毛猎犬和10只其它犬种的HS进行了突变检测和流行病学分析。PTPN 11（E76 K）在骨密度异常的HS中的总检出率为36.67%，而在其他品种中的总检出率为8.69%。在10只携带突变的HS的BMD和12只无肿瘤疾病的对照犬（包括6只BMD）的正常组织中未发现突变。在PTPN 11（E76 K）的一小部分BMD中，AKT、磷酸化ERK 1/2和磷酸化AKT的免疫反应性增加，表明功能获得可能由ERK和AKT通路介导。这些数据表明PTPN 11（E76 K）是BMD中HS的重要驱动突变。这些信息不仅有助于解开与骨密度相关的肿瘤发生事件，而且有助于确定更有前途的治疗策略。
Histiocytic sarcoma (HS) is an aggressive malignant neoplasm of dendritic cell origin that is common in certain breeds of dogs. High prevalence of fatal, disseminated HS has been described in Bernese Mountain Dogs (BMDs). Support for genetic predisposition to develop HS has been presented in several studies, but to date, causative genetic events have not been reported. In addition, no driver mutations have been identified in tumours. Recently, E76K gain-of-function mutation in SHP2 encoded by the PTPN11 gene has been described in human histiocytic malignancies. In our study, we identified the PTPN11(E76K) in HS of BMDs. Amplification of exon 3 of the PTPN11 gene followed by Sanger sequencing was used to detect the mutation and estimate the prevalence in HS from 30 BMDs, 13 Golden Retrievers and 10 other dog breeds. The overall prevalence of PTPN11(E76K) in HS of BMDs was 36.67% compared with 8.69% in other breeds. No mutation was identified in normal tissues from 10 BMDs with HS that carried the mutation and 12 control dogs with no neoplastic disease, including 6 BMDs. Increased immunoreactivity for AKT, phosphorylated ERK1/2 and phosphorylated AKT in a small subset of BMDs with PTPN11(E76K) suggests that a gain-of-function might be mediated by the ERK and AKT pathways. These data suggest PTPN11(E76K) as an important driver mutation of HS in BMDs. This information may not only aid in unravelling the tumourigenic events associated with HS in BMDs, but also help in identifying more promising therapeutic strategies.