WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.
WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.
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DOI：
10.1056/nejmoa1914919
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发表时间：
2020-05-28
期刊：
影响因子：
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通讯作者：
Pandolfi PP
中科院分区：
文献类型：
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作者：
Lee YR;Yehia L;Kishikawa T;Ni Y;Leach B;Zhang J;Panch N;Liu J;Wei W;Eng C;Pandolfi PP
患有PTEN错构瘤肿瘤综合征（PHTS）的患者在编码磷酸酶和张力蛋白同源物（PTEN）的肿瘤抑制基因中具有种系突变。这种突变与多种类型癌症的遗传易感性有关，包括考登综合征。然而，大多数具有PHTS相关表型的患者对PTEN突变的检测呈阴性。在先前的研究中，我们发现E3泛素连接酶WWP 1负调控PTEN的功能。在2005年至2015年进行的一项前瞻性队列研究中，我们招募了431名至少符合国际考登联盟宽松诊断标准的野生型PTEN患者。对患者进行WWP 1生殖系变异扫描。我们使用癌症基因组图谱（TCGA）数据集作为明显散发性癌症的代表，并使用外显子组聚集联盟数据集（不包括TCGA（非TCGA ExAC））和非癌症基因组聚集数据库（gnomAD）作为没有报告癌症诊断的人群对照的代表。我们建立了体外和小鼠体内模型，以功能表征代表性WWP 1变体。种系WWP 1变体的存在首先在一个患有寡息肉病和早发性结肠癌的野生型PTEN家族中建立。一个验证系列表明，WWP 1种系变异发生在126例无关患者中的5例（4%），以寡息肉病为主要表型。生殖系WWP 1变异，特别是WWP 1 K740 N和N745 S等位基因，在没有PHTS但患有散发性癌症的患者中富集，包括TCGA中的PTEN相关癌症类型（比值比，1.5; 95%置信区间，1.1至2.1; P = 0.01）。优先的WWP 1变体导致功能获得效应，这导致异常的酶激活，随后是PTEN失活，从而在细胞和鼠模型中触发过度活跃的促进生长的PI 3 K信号传导。在这项研究中，涉及患者的疾病导致的倾向，以发展多种恶性肿瘤没有PTEN种系突变，我们证实了WWP 1作为一个癌症易感基因的功能，通过直接异常调节的PTEN-PI 3 K信号转导轴。（由美国国立卫生研究院和其他机构资助。
Patients with PTEN hamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (PTEN). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative for PTEN mutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN. In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-type PTEN who met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned for WWP1 germline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representative WWP1 variants. The existence of germline WWP1 variants was first established in a family with wild-type PTEN who had oligopolyposis and early-onset colon cancers. A validation series indicated that WWP1 germline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germline WWP1 variants, particularly the WWP1 K740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including PTEN-related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritized WWP1 variants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models. In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms without PTEN germline mutations, we confirmed the function of WWP1 as a cancer-susceptibility gene through direct aberrant regulation of the PTEN–PI3K signaling axis. (Funded by the National Institutes of Health and others.)