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散发性脑海绵状血管畸形的体细胞PIK3CA突变
Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations


Matthieu Peyre ... 其他 • 2021.09.09

摘要


背景

脑海绵状血管畸形(CCM)是常见的散发性和遗传性中枢神经系统血管畸形。家族性CCM与KRIT1CCM1)、CCM2PDCD10CCM3)的失活突变相关,而占全部病例80%的散发性CCM的遗传原因尚未完全明了。

 

方法

我们应用前列腺素D2合成酶(PGDS)启动子开发了携带人类脑膜瘤中所发现突变的两种小鼠模型。我们对患者的手术切除CCM进行了靶向DNA测序,并通过液滴数字聚合酶链反应分析法证实了我们的发现。

 

结果

我们发现,PGDS阳性细胞表达脑膜瘤两种常见驱动基因(Pik3caH1047RAKT1E17K)之一的小鼠发生了典型的CCM谱系疾病(分别见于22%和11%的小鼠),而非脑膜瘤,这促使我们分析了88例患者的散发性CCM的组织样本。在这些患者的病变组织中,我们分别在39%和1%中检测出体细胞PIK3CAAKT1激活突变。仅有10%的病变携带CCM基因突变。我们在小鼠中分析了激活突变Pik3caH1047RAKT1E17K诱导产生的病变,并发现表达PGDS的周细胞可能是起源细胞。

 

结论

在散发性CCM的组织样本中,PIK3CA突变的占比超过任何其他基因的突变。家族性CCM致病基因的体细胞突变发挥的作用相对较小(由ARC癌症研究基金会[Fondation ARC pour la Recherche contre le Cancer]等资助)。





作者信息

Matthieu Peyre, M.D., Ph.D., Danielle Miyagishima, Ph.D., Franck Bielle, M.D., Ph.D., Françoise Chapon, M.D., Ph.D., Michael Sierant, Ph.D., Quitterie Venot, Ph.D., Julie Lerond, M.Sc., Pauline Marijon, M.D., Samiya Abi-Jaoude, M.D., Tuan Le Van, M.D., Karim Labreche, Ph.D., Richard Houlston, Ph.D., Maxime Faisant, M.D., Ph.D., Stéphane Clémenceau, M.D., Anne-Laure Boch, M.D., Aurelien Nouet, M.D., Alexandre Carpentier, M.D., Ph.D., Julien Boetto, M.D., Angeliki Louvi, Ph.D., and Michel Kalamarides, M.D., Ph.D.
From the Departments of Neurosurgery (M.P., S.C., A.-L.B., A.N., A.C., M.K.) and Neuropathology (F.B.), Sorbonne Université, Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, INSERM Unité 1127, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7225, Paris Brain Institute (M.P., F.B., J.L., P.M., S.A.-J., T.L.V., K.L., J.B., M.K.), and INSERM Unité 1151–Institut Necker Enfants Malades, Hôpital Necker Enfants Malades, AP-HP (Q.V.), Paris, and the Department of Pathology, Centre Hospitalier Régional Universitaire (CHRU) Caen–INSERM Unité 1075 COMETE, Caen University (F.C.), and the Department of Pathology CHRU Caen–INSERM Unité Mixte de Recherche en Santé Unité 1237, Cyceron (M.F.), Caen — all in France; the Departments of Genetics (D.M., M.S.) and Neurosurgery and Neuroscience (A.L.), Yale School of Medicine, New Haven, CT; and the Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom (K.L., R.H.). Address reprint requests to Dr. Peyre or Dr. Kalamarides at the Department of Neurosurgery, AP-HP, Hôpital Pitié Salpêtrière, 47-91 bd de l’Hôpital, 75013 Paris, France, or at matthieu.peyre@aphp.fr or michel.kalamarides@aphp.fr.

 

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