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WWP1获得功能导致的PTEN失活在癌症易感性中的作用
WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition


Yu-Ru Lee ... 肿瘤 • 2020.05.28

摘要


背景

PTEN错构瘤综合征(PHTS)患者中,编码磷酸酯酶与张力蛋白同源物的肿瘤抑制基因(PTEN)有生殖细胞系突变。此类突变被认为与多种癌症(包括Cowden综合征)的遗传易感性相关。然而,在具有PHTS相关表型的患者中,大多数的PTEN突变检测结果呈阴性。在之前的一项研究中,我们发现E3泛素连接酶WWP1能够负调控PTEN的功能。

 

方法

在2005—2015年开展的一项前瞻性队列研究中,我们纳入了至少符合国际Cowden联盟(International Cowden Consortium)宽松诊断标准并且有野生型PTEN基因的431例患者。我们对患者进行了扫描,确定其是否有WWP1生殖细胞系变异体。我们使用癌症基因组图谱(Cancer Genome Atlas,TCGA)的数据集代表表面上散发的癌症,使用不包括TCGA的外显子组集合数据库(Exome Aggregation Consortium)(非TCGA ExAC)的数据集和非癌症基因组聚合数据库(Genome Aggregation Database,gnomAD)代表未报告癌症诊断的人群对照。我们建立了体外模型和小鼠体内模型,以确定代表性WWP1变异体的功能特征。

 

结果

生殖细胞系WWP1变异体最早是在一个患少息肉病(oligopolyposis)和早发性结肠癌,并且有野生型PTEN的家系中发现。一个验证系列研究表明,在少息肉病为主要表现型且并无血缘关系的126例患者中,5例(4%)有WWP1生殖细胞系变异体。在患高发的散发性癌症(包括TCGA中的PTEN相关癌症类型),但无PHTS的患者中,生殖细胞系WWP1变异体(特别是WWP1 K740N和N745S等位基因)富集(比值比,1.5;95%置信区间[CI],1.1~2.1;P=0.01)。优先关注的WWP1变异体产生了功能获得效应,导致了异常的酶激活和随后的PTEN失活,从而在细胞和小鼠模型中触发了对过度生长有促进作用的PI3K信号传导。

 

结论

本研究纳入了无PTEN生殖细胞系突变,但其异常可导致多种恶性肿瘤易感性的患者,结果证明了作为癌症易感基因的WWP1通过直接异常调控PTEN-PI3K信号轴所发挥的功能(由美国国立卫生研究院等资助)。





作者信息

Yu-Ru Lee, Ph.D., Lamis Yehia, Ph.D., Takahiro Kishikawa, M.D., Ph.D., Ying Ni, Ph.D., Brandie Leach, M.S., Jinfang Zhang, Ph.D., Nivedita Panch, M.S., Jing Liu, Ph.D., Wenyi Wei, Ph.D., Charis Eng, M.D., Ph.D., and Pier Paolo Pandolfi, M.D., Ph.D.
From the Cancer Research Institute, Beth Israel Deaconess Cancer Center (Y.-R.L., T.K., J.Z., N.P., J.L., W.W., P.P.P.), and the Departments of Medicine (Y.-R.L., T.K., N.P., P.P.P.) and Pathology (J.Z., J.L., W.W., P.P.P.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston; the Genomic Medicine Institute (L.Y., Y.N., B.L., C.E.) and the Department of Quantitative Health Sciences (Y.N.), Lerner Research Institute, Cleveland Clinic, the Taussig Cancer Institute (C.E.), the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine (C.E.), and the Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University (C.E.) — all in Cleveland; the Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University (J.Z.), and the Medical Research Institute, Wuhan University (J.Z.) — both in Wuhan, China; and the Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy (P.P.P.). Address reprint requests to Dr. Pandolfi at the Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin 10126, Italy, or at pierpaolo.pandolfiderinaldis@unito.it; or to Dr. Eng at the Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, or at engc@ccf.org.

 

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