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PTPN11 mutations in canine and human disseminated histiocytic sarcoma.
International Journal of Cancer ( IF 5.7 ) Pub Date : 2020-03-25 , DOI: 10.1002/ijc.32991
Benoit Hédan 1 , Mélanie Rault 1 , Jérôme Abadie 2 , Ronan Ulvé 1 , Nadine Botherel 1 , Patrick Devauchelle 3 , Christiane Copie-Bergman 4, 5 , Edouard Cadieu 1 , Marie Parrens 6 , Julia Alten 7 , Emmanuelle L Zalcman 8 , Gunnar Cario 7 , Gandhi Damaj 9 , Karima Mokhtari 10 , Francois Le Loarer 11 , Aurore Coulomb-Lhermine 12 , Thomas Derrien 1 , Christophe Hitte 1 , Laura Bachelot 1 , Matthew Breen 13 , David Gilot 1 , Jean Y Blay 11 , Jean Donadieu 14 , Catherine André 1
Affiliation  

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS ( 7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti‐proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.

中文翻译:

犬和​​人播散的组织细胞肉瘤中的PTPN11突变。

在人类中,组织细胞肉瘤(HS)是一种侵袭性癌症,涉及组织细胞。其稀有性和异质性说明治疗仍然是一个挑战。相反,犬HS在特定品种中与人类HS有着高度的临床和组织病理学相似性,因此它构成了人类HS独特的自发模型,以破译其遗传基础并探索治疗选择。我们在至少63.9%(71/111)的HS病例中发现了MAPK通路的序列改变,其中HSAF分别为互斥的BRAF(0.9%; 1/111),KRAS( 7.2%; 8/111)和PTPN11(56.75%; 63) / 111)突变集中在人类癌症常见的热点。复发性PTPN11突变与犬的内脏弥漫性HS亚型有关,这是最积极的临床表现。然后,我们在3/19(15.7%)的人类HS患者中鉴定了PTPN11突变。因此,我们建议将PTPN11突变作为人和犬HS特定子集的关键事件:内脏播散形式。最后,通过在八种犬HS细胞系中测试靶向MAPK途径的药物,我们确定了犬HS肿瘤细胞中MEK抑制剂的抗增殖活性优于PTPN11抑制剂。综合起来,这些结果说明了自然受感染的狗在破译遗传机制和选择有效的靶向疗法以治疗人类这种罕见和侵袭性癌症方面的相关性。
更新日期:2020-03-25
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