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WWP1功能获得性失活PTEN的肿瘤易感性
作者:小柯机器人 发布时间:2020/5/28 17:26:55

意大利都灵大学Pier Paolo Pandolfi联合美国克利夫兰诊所Charis Eng团队发现WWP1功能获得性失活PTEN的肿瘤易感性。该成果发表在2020年5月28日出版的《新英格兰医学杂志》上。

患有PTEN错构瘤综合征(PHTS)的患者在编码磷酸酶-张力蛋白同源物(PTEN)的肿瘤抑制基因中存在种系突变。此类突变与多种癌症的遗传易感性有关,包括考登综合症。但大多数PHTS相关表型的患者PTEN突变检测均为阴性。此前研究组发现E3泛素连接酶WWP1可负调控PTEN的功能。

在2005-2015年进行的一项前瞻性队列研究中,研究组招募了431位野生型PTEN患者,这些患者至少符合国际考登协会的宽松诊断标准。对患者的WWP1种系变体进行扫描。研究组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,不包括TCGA(非TCGA-ExAC)的外显子集合数据集和非癌基因组聚集数据库(gnomAD)作为非癌人群对照代表。研究组建立了体外和小鼠体内模型,以功能性表征代表性的WWP1变体。

WWP1基因变异的存在,首先建立在患有少息肉病和早期结肠癌的野生型PTEN家族中。验证系列结果表明,在126名不相关患者中,有5名(4%)以少息肉病为主要表型,发生了WWP1种系变异。种系WWP1变异,特别是WWP1 K740N和N745S等位基因,在没有PHTS但患有广泛散发性癌症(包括TCGA中PTEN相关的癌症类型)的患者中富集。WWP1优先变异造成功能获得效应,导致异常的酶促激活和PTEN失活,从而在细胞和小鼠模型中触发高活性促生长PI3K信号。

总之,研究组通过PTEN-PI3K信号轴的直接异常调节,证实了WWP1作为一种癌症易感基因的功能,该基因涉及那些易患多发性恶性肿瘤且无PTEN种系突变的患者。

附:英文原文

Title: WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition

Author: 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.

Issue&Volume: 2020-05-27

Abstract: Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

DOI: 10.1056/NEJMoa1914919

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1914919

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home