Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2012 Feb;25(2):212-21. doi: 10.1038/modpathol.2011.148. Epub 2011 Oct 21.
The molecular determinants involved in the progression of myxoid liposarcoma to increased cellularity/round cell change are poorly understood. We studied the PI3K/Akt pathway in myxoid and round cell liposarcomas using a tissue microarray composed of 165 tumors from 111 patients, and mutational analysis of PIK3CA in 44 cases. Activating PIK3CA mutations were found in 6/44 cases, 14%; mutations were more frequent in round cell vs myxoid tumors (5/15, 33% vs 1/29, 3%; P=0.013). Complete loss of PTEN, an alternative mechanism for PI3K/Akt activation, was found in 13/111 (12%) cases and was mutually exclusive with PIK3CA mutation. Strong IGF1R expression was demonstrated in 14/39 (36%) of round cell and 11/58 (19%) of myxoid tumors (P=0.062). Activation of the PI3K pathway was confirmed using immunohistochemical analysis for downstream targets phospho-S6 ribosomal protein and phospho-4EBP1. Phospho-4EBP1 was increased in round cell tumors compared with myxoid tumors (24/30, 80% vs 25/44, 57%; P=0.038) or tumors with treatment effect (10/24, 42%; P=0.02). Phospho-S6 was highly expressed in both myxoid and round cell tumors (29/47, 62% and 14/30, 47%, respectively; P=0.2). In tumors with PIK3CA mutation, any IGF1R expression, or loss of PTEN expression, phospho-4EBP1 was more frequently elevated compared with tumors without a known activating event in the PI3K pathway (55/72; 76% vs 3/8, 38%; P=0.033). These findings suggest that activation of the PI3K/Akt pathway via activating mutation of PIK3CA, loss of PTEN, or IGF1R expression have a role in round cell transformation. The PI3K/Akt pathway may therefore provide a therapeutic target in round cell liposarcoma.
在黏液样脂肪肉瘤向细胞增多/圆形细胞变化进展中涉及的分子决定因素了解甚少。我们使用由 111 例患者的 165 例肿瘤组成的组织微阵列研究了黏液样和圆形细胞脂肪肉瘤中的 PI3K/Akt 途径，并对 44 例病例中的 PIK3CA 进行了突变分析。在 44 例病例中发现了 6 例（14%）存在激活性 PIK3CA 突变，在圆形细胞肿瘤中突变更常见（5/15，33%比 29/29，3%；P=0.013）。在 111 例病例中有 13 例（12%）发现完全缺失 PTEN，这是 PI3K/Akt 激活的另一种机制，与 PIK3CA 突变相互排斥。在 39 例圆形细胞肿瘤中有 14 例（36%）和 58 例黏液样肿瘤中有 11 例（19%）（P=0.062）显示出强烈的 IGF1R 表达。使用免疫组织化学分析下游靶标磷酸化 S6 核糖体蛋白和磷酸化 4EBP1 证实了 PI3K 途径的激活。与黏液样肿瘤相比，磷酸化 4EBP1 在圆形细胞肿瘤中增加（30/30，80%比 44/44，57%；P=0.038）或在有治疗效果的肿瘤中增加（24/24，42%；P=0.02）。磷酸化 S6 在黏液样和圆形细胞肿瘤中均高度表达（分别为 29/47，62%和 14/30，47%；P=0.2）。在具有 PIK3CA 突变、任何 IGF1R 表达或 PTEN 表达缺失的肿瘤中，与在 PI3K 途径中没有已知激活事件的肿瘤相比，磷酸化 4EBP1 更频繁升高（55/72，76%比 8/8，38%；P=0.033）。这些发现表明，PI3K/Akt 途径的激活通过 PIK3CA 的激活突变、PTEN 的缺失或 IGF1R 的表达在圆形细胞转化中起作用。因此，PI3K/Akt 途径可能为圆形细胞脂肪肉瘤提供治疗靶点。
