Marsit Carmen J, Zheng Shichun, Aldape Kenneth, Hinds Philip W, Nelson Heather H, Wiencke John K, Kelsey Karl T
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Hum Pathol. 2005 Jul;36(7):768-76. doi: 10.1016/j.humpath.2005.05.006.
The tumor suppressor PTEN encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase/AKT cell survival pathway. Mutations of this gene are common in brain, prostate, endometrial, and gastric cancers but occur rarely in non-small-cell lung cancer (NSCLC), although the PTEN protein is often lost in lung tumors. We have studied hypermethylation of the PTEN promoter, loss of heterozygosity (LOH) at microsatellites in chromosome 10q23 (surrounding and intragenic to the PTEN locus), and hypermethylation of PTEN's highly homologous pseudogene, PTENP1, and their association with PTEN protein loss in a surgical case series study of primary NSCLC. PTEN protein expression was reduced or lost in 74% (86/117) of tumors, with loss occurring more often in well to moderately differentiated tumors. In squamous cell carcinomas, PTEN loss occurred significantly more often in early-stage (stage I or II) disease. PTEN protein loss also occurred more frequently in tumors with low to no aberrant TP53 staining. Methylation of PTEN occurred in 26% (39/151) of tumors, and LOH at 10q23 was rare, occurring in only 19% (17/90) of informative tumors. Neither methylation nor LOH was a significant predictor of PTEN protein expression, although LOH occurred exclusively in early-stage disease. In NSCLC, loss of PTEN protein expression occurs frequently, although the mechanism responsible for loss is not clearly attributable to deletion or epigenetic silencing. PTEN loss may also be a favorable prognostic marker, although further studies are needed to confirm this finding.
肿瘤抑制基因PTEN编码一种脂质磷酸酶，该酶对磷脂酰肌醇3激酶/AKT细胞存活通路起负调控作用。该基因的突变在脑癌、前列腺癌、子宫内膜癌和胃癌中很常见，但在非小细胞肺癌（NSCLC）中很少发生，尽管PTEN蛋白在肺肿瘤中常常缺失。我们在一项原发性NSCLC手术病例系列研究中，研究了PTEN启动子的高甲基化、10q23染色体微卫星处的杂合性缺失（LOH）（PTEN基因座周围及基因内）以及PTEN高度同源假基因PTENP1的高甲基化，及其与PTEN蛋白缺失的相关性。74%（86/117）的肿瘤中PTEN蛋白表达降低或缺失，在高分化至中分化肿瘤中缺失更常见。在鳞状细胞癌中，PTEN缺失在早期（I期或II期）疾病中显著更常见。PTEN蛋白缺失在低至无异常TP53染色的肿瘤中也更频繁发生。26%（39/151）的肿瘤中发生了PTEN甲基化，10q23处的LOH很少见，仅在19%（17/90）的信息性肿瘤中出现。甲基化和LOH均不是PTEN蛋白表达的显著预测指标，尽管LOH仅发生在早期疾病中。在NSCLC中，PTEN蛋白表达缺失很常见，尽管导致缺失的机制尚不清楚是由于缺失还是表观遗传沉默。PTEN缺失也可能是一个有利的预后标志物，尽管需要进一步研究来证实这一发现。
