Eng Charis
Clinical Cancer Genetics Program and Human Cancer Genetics Program, Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Hum Mutat. 2003 Sep;22(3):183-98. doi: 10.1002/humu.10257.
PTEN, on 10q23.3, encodes a major lipid phosphatase which signals down the phosphoinositol-3-kinase/Akt pathway and effects G1 cell cycle arrest and apoptosis. Germline PTEN mutations have been found to occur in 80% of classic Cowden syndrome (CS), 60% of Bannayan-Riley-Ruvalcaba syndrome (BRRS), up to 20% of Proteus syndrome (PS), and approximately 50% of a Proteus-like syndrome (PSL). CS is a heritable multiple hamartoma syndrome with a high risk of breast, thyroid, and endometrial carcinomas. BRRS is a congenital autosomal dominant disorder characterized by megencephaly, developmental delay, lipomatosis, and speckled penis. PS and PSL had never been associated with risk of malignancy. Finding germline PTEN mutations in patients with BRRS, PS, and PSL suggests equivalent risks of developing malignancy as in CS with implications for medical management. The mutational spectra of CS and BRRS overlap, with many of the mutations occurring in exons 5, 7, and 8. Genotype-phenotype association analyses have revealed that the presence of germline PTEN mutations is associated with breast tumor development, and that mutations occurring within and 5' of the phosphatase motif were associated with multi-organ involvement. Pooled analysis of PTEN mutation series of CS and BRRS occurring in the last five years reveals that 65% of CS-associated mutations occur in the first five exons encoding the phosphatase domain and the promoter region, while 60% of BRRS-associated mutations occur in the 3' four exons encoding mainly the C2 domain. Somatic PTEN mutations occur with a wide distribution of frequencies in sporadic primary tumors, with the highest frequencies in endometrial carcinomas and glioblastoma multiform. Several mechanisms of PTEN inactivation occur in primary malignancies derived from different tissues, but a favored mechanism appears to occur in a tissue-specific manner. Inappropriate subcellular compartmentalization and increased/decreased proteosome degradation may be two novel mechanisms of PTEN inactivation. Further functional work could reveal more effective means of molecular-directed therapy and prevention.
位于10q23.3的PTEN编码一种主要的脂质磷酸酶，该酶通过磷酸肌醇-3-激酶/蛋白激酶B（Akt）信号通路发挥作用，从而影响G1期细胞周期停滞和细胞凋亡。已发现80%的典型考登综合征（CS）、60%的巴纳扬-莱利-鲁瓦尔卡巴综合征（BRRS）、高达20%的变形综合征（PS）以及约50%的类变形综合征（PSL）存在种系PTEN突变。CS是一种遗传性多发性错构瘤综合征，患乳腺癌、甲状腺癌和子宫内膜癌的风险较高。BRRS是一种先天性常染色体显性疾病，其特征为巨头畸形、发育迟缓、脂肪瘤病和阴茎斑点。PS和PSL此前从未被认为与恶性肿瘤风险相关。在BRRS、PS和PSL患者中发现种系PTEN突变表明，其发生恶性肿瘤的风险与CS相当，这对医疗管理具有重要意义。CS和BRRS的突变谱重叠，许多突变发生在外显子5、7和8中。基因型-表型关联分析显示，种系PTEN突变的存在与乳腺肿瘤发生相关，而磷酸酶基序内及5'端的突变与多器官受累相关。对过去五年中发生的CS和BRRS的PTEN突变系列进行汇总分析发现，65%的CS相关突变发生在编码磷酸酶结构域和启动子区域的前五个外显子中，而60%的BRRS相关突变发生在主要编码C2结构域的3'端四个外显子中。体细胞PTEN突变在散发性原发性肿瘤中的发生频率分布广泛，在子宫内膜癌和多形性胶质母细胞瘤中频率最高。PTEN失活的几种机制发生在源自不同组织的原发性恶性肿瘤中，但一种常见机制似乎以组织特异性方式发生。不适当的亚细胞区室化以及蛋白酶体降解增加/减少可能是PTEN失活的两种新机制。进一步的功能研究可能会揭示更有效的分子导向治疗和预防手段。
