Functions and Regulation of the PTEN Gene in Colorectal Cancer.
Functions and Regulation of the PTEN Gene in Colorectal Cancer.
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DOI：
10.3389/fonc.2013.00326
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发表时间：
2013
影响因子：
4.7
通讯作者：
Frattini M
中科院分区：
文献类型：
--
作者：
Molinari F;Frattini M
10号染色体上缺失的磷酸酶和张力蛋白酶同源物（PTEN）是位于染色体10q23.31的肿瘤抑制基因，编码具有脂质和蛋白磷酸酶活性的403个氨基酸的蛋白。PTEN的主要功能是通过将磷脂酰肌醇（PI）3，4，5-三磷酸去磷酸化为PI-4，5-二磷酸从而抵消PI 3 K功能来阻断PI 3 K途径。PTEN失活是许多癌症类型中的常见事件，并且可以通过各种遗传改变发生，包括点突变、大染色体缺失和表观遗传机制。在结直肠癌（CRC）中，PTEN通过混合的遗传/表观遗传机制（通常：突变和启动子超甲基化或10 q23洛和启动子超甲基化）改变，这导致20-30%的病例中蛋白质的双等位基因失活。相对较少的研究报道了PTEN作为CRC预后和预测因子的作用。本评论的重点是报告和讨论的研究调查这些方面。总的来说，目前，有相互矛盾的结果，因此尚未澄清PTEN是否可能在CRC中发挥预后作用。这同样适用于预测作用，导致PTEN评估不能用于常规诊断，以早期识别可能接受EGFR靶向治疗的患者，这与属于EGFR下游途径的其他遗传改变不一致。不一致结果的原因可能归因于几个问题：（1）分析队列的大小，（2）患者纳入标准，（3）评估PTEN改变的方法。特别是，没有标准化的方法来评估这种标志物，特别是对于免疫组织化学，由于这种分析的半定量特征，这种技术遭受观察者内和观察者间的变化。总之，在建立PTEN作为结直肠癌预后或预测标志物之前，必须做大量工作，特别是在来自不同实验室的大型同质病例队列中。
Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene located at chromosome 10q23.31, encoding for a 403-amino acid protein that possesses both lipid and protein phosphatase activities. The main function of PTEN is to block the PI3K pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. PTEN inactivation is a frequent event in many cancer types and can occur through various genetic alterations including point mutations, large chromosomal deletions, and epigenetic mechanisms. In colorectal cancer (CRC) PTEN is altered through mixed genetic/epigenetic mechanisms (typically: mutations and promoter hypermethylation or 10q23 LOH and promoter hypermethylation), which lead to the biallelic inactivation of the protein in 20–30% of cases. The role of PTEN as a prognostic and predictive factor in CRC has been addressed by relatively few works. This review is focused on the report and on the discussion of the studies investigating these aspects. Overall, at the moment, there are conflicting results and, therefore it has not been clarified whether PTEN might play a prognostic role in CRC. The same is valid also for the predictive role, leading to the fact that PTEN evaluation cannot be used in routinely diagnosis for the early identification of patients who might be addressed to the treatment with EGFR-targeted therapies, at odds with other genetic alterations belonging to EGFR-downstream pathways. The reason of discordant results may be attributable to several issues: (1) the size of the analyzed cohort, (2) patients inclusion criteria, (3) the methods of assessing PTEN alteration. In particular, there are no standardized methods to evaluate this marker, especially for immunohistochemistry, a technique suffering of intra and inter-observer variability due to the semi-quantitative character of such an analysis. In conclusion, much work, especially in large and homogeneous cohorts of cases from different laboratories, has to be done before the establishment of PTEN as prognostic or predictive marker in CRC.