PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
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DOI：
10.1158/1078-0432.ccr-06-1609
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发表时间：
2007-06-15
影响因子：
11.5
通讯作者：
Stal, Olle
中科院分区：
文献类型：
--
作者：
Perez-Tenorio, Gizeh;Alkhori, Liza;Stal, Olle
目的：磷脂酰肌醇3'-激酶/蛋白激酶B（Akt）通路在乳腺癌中经常发生改变。第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）是一种可对抗磷脂酰肌醇S -激酶作用的磷酸酶，它可能发生突变或缺失，而磷脂酰肌醇-4,5 -二磷酸3 -激酶催化亚基α（PIK3CA）基因会发生突变。这些已被提议作为替代机制，它们的临床病理意义正在讨论中。在本研究中，我们旨在探讨PIK3CA突变和PTEN缺失是否为相互排斥的机制，是否与其他已知的临床病理标志物相关，以及在乳腺癌中是否具有临床意义。
实验设计：对270例乳腺肿瘤的PIK3CA基因第9和20外显子进行分析，通过单链构象分析及后续测序检测突变。通过免疫组化对201例肿瘤评估PTEN的表达。
结果：在24%的肿瘤中发现PIK3CA突变，且与雌激素受体（ER）阳性状态、肿瘤体积小、人表皮生长因子受体2（HER2）阴性状态、Akt1高表达以及细胞周期蛋白D1蛋白高表达相关。37%的病例中PTEN呈阴性，且PTEN缺失与PIK3CA突变相关（P = 0.0024）。出现PTEN缺失或两种改变均有的肿瘤通常为雌激素受体阳性、体积小且HER2阴性。PIK3CA突变预示局部无复发生存期更长。此外，PTEN缺失本身或与突变的PIK3CA相结合往往赋予放射敏感性。另外，S期细胞比例高的患者如果携带PIK3CA基因突变和/或PTEN缺失，则无复发生存期更长，而在S期细胞比例低的患者中，相同的改变与无复发生存期较短相关。
结论：PIK3CA突变和PTEN缺失并非相互排斥的事件，且与相似的预后因素相关。
Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol S-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer.Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors.Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor+, small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction.Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.