文章：

PTEN在常见癌症、罕见综合征和小鼠模型中的连续缺失

PTEN loss in the continuum of common cancers, rare syndromes and mouse models

原文发布日期：2011-03-24

DOI: 10.1038/nrc3037

类型: Review Article

开放获取: 否

要点：

1. PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations. The range of abnormalities in patients with PHTS varies from patient to patient.
2. Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types. These include the classical PHTS-associated tumours like breast, endometrium and thyroid, but also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma.
3. Mouse models of Cowden syndrome, in which a single allele of Pten is deleted or mutated, exhibit characteristic Cowden syndrome phenotypes. Tumour types are very much dependent on the genetic background of the mice suggesting that there may be genetic risk factors for PHTS penetrance in humans.
4. Tissue-specific deletion of Pten in mice can lead to rapid, slow or no tumours, depending on the tissue type. In some cases, tissue-specific Pten deletion can cooperate with other genetic alterations to enhance tumorigenesis. These mouse models have validated mutation or loss of PTEN as an aetiological factor in similar human tumours.
5. PTEN is a lipid phosphatase that acts as a negative regulator of the PI3K–AKT–mTOR pathway, which is an important regulator of cell growth and survival. As such, pharmacological inhibition of this pathway may be exploited for therapy of tumours with altered PTEN, or for tumour prevention in patients with PHTS.

要点翻译：

1. PTEN错构瘤肿瘤综合征（PHTS）是一组以良性增生为特征，并伴随乳腺癌、子宫内膜癌和甲状腺癌高发风险的综合征。其中Cowden综合征的特征最为明确，85%的患者存在PTEN基因种系突变。PHTS患者的异常表现范围因人而异。
2. 体细胞PTEN突变与缺失，以及通过甲基化或微RNA沉默导致PTEN失活的现象在多种肿瘤类型中十分常见。这些肿瘤既包括典型的PHTS相关肿瘤（如乳腺、子宫内膜和甲状腺肿瘤），也涉及中枢神经系统、前列腺、肺、胰腺、肝脏和肾上腺的肿瘤，还包括黑色素瘤、白血病和淋巴瘤。
3. 在Cowden综合征小鼠模型中，单个Pten等位基因的缺失或突变会呈现典型Cowden综合征表型。肿瘤类型高度依赖于小鼠的遗传背景，这提示人类PHTS外显率可能存在遗传风险因素。
4. 小鼠组织特异性Pten缺失可能根据组织类型引发快速、缓慢或零肿瘤发生。在某些情况下，组织特异性Pten缺失可与其他遗传改变协同促进肿瘤发生。这些小鼠模型证实了PTEN突变或缺失是人类类似肿瘤的病因学因素。
5. PTEN作为一种脂质磷酸酶，是PI3K-AKT-mTOR通路的负向调控因子，该通路是细胞生长与存活的重要调节器。因此，通过药物抑制该通路或可用于治疗PTEN突变肿瘤，或为PHTS患者提供肿瘤预防策略。

英文摘要：

PTEN is among the most frequently inactivated tumour suppressor genes in sporadic cancer. PTEN has dual protein and lipid phosphatase activity, and its tumour suppressor activity is dependent on its lipid phosphatase activity, which negatively regulates the PI3K–AKT–mTOR pathway. Germline mutations in PTEN have been described in a variety of rare syndromes that are collectively known as the PTEN hamartoma tumour syndromes (PHTS). Cowden syndrome is the best-described syndrome within PHTS, with approximately 80% of patients having germline PTEN mutations. Patients with Cowden syndrome have an increased incidence of cancers of the breast, thyroid and endometrium, which correspond to sporadic tumour types that commonly exhibit somatic PTEN inactivation. Pten deletion in mice leads to Cowden syndrome-like phenotypes, and tissue-specific Pten deletion has provided clues to the role of PTEN mutation and loss in specific tumour types. Studying PTEN in the continuum of rare syndromes, common cancers and mouse models provides insight into the role of PTEN in tumorigenesis and will inform targeted drug development.

摘要翻译： 

PTEN是散发性癌症中最常失活的抑癌基因之一。PTEN具有蛋白和脂质双重磷酸酶活性，其抑癌功能依赖于其脂质磷酸酶活性，该活性可负向调控PI3K–AKT–mTOR通路。PTEN的胚系突变可见于多种罕见综合征，统称为PTEN错构瘤肿瘤综合征（PHTS）。Cowden综合征是PHTS中描述最清楚的综合征，约80%的患者携带PTEN胚系突变。Cowden综合征患者乳腺癌、甲状腺癌和子宫内膜癌的发病率升高，这些癌种对应常见且常出现PTEN体细胞失活的散发性肿瘤类型。小鼠Pten缺失可产生类似Cowden综合征的表型，组织特异性Pten缺失揭示了PTEN突变和缺失在特定肿瘤中的作用。在罕见综合征、常见癌症和动物模型中研究PTEN，有助于理解其在肿瘤发生中的作用，并指导靶向药物开发。

原文链接：

PTEN loss in the continuum of common cancers, rare syndromes and mouse models