Oda Yoshinao, Yamamoto Hidetaka, Takahira Tomonari, Kobayashi Chikashi, Kawaguchi Kenichi, Tateishi Naomi, Nozuka Yoko, Tamiya Sadafumi, Tanaka Kazuhiro, Matsuda Shuichi, Yokoyama Ryohei, Iwamoto Yukihide, Tsuneyoshi Masazumi
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Pathol. 2005 Dec;207(4):410-21. doi: 10.1002/path.1848.
In myxoid/round cell liposarcoma (MLS/RCLS), the presence of a round cell (RC) component has been reported to correlate with a worse prognosis for the patients. However, little is known about the molecular genetic differences between conventional myxoid (MX) components and RC components in this tumour. The aim of this study was to investigate the possible implications of molecular alterations of G1 to S-phase check-point genes, especially in the RC component. We evaluated the immunohistochemical expression of p53, MDM2, p14 and p16 protein and assessed proliferative activities using MIB-1 in 29 RC components and 81 MX components from 90 cases. Mutation of the p53 gene, amplification of the MDM2 gene, homozygous deletion, methylation status and mutation of the p16(INK4a)/p14(ARF) genes were also investigated, using concordant paraffin-embedded and frozen material. The data were analysed together with clinicopathological factors to assess their prognostic implications in MLS/RCLS. Immunohistochemically, the over-expression of p53 protein (p = 0.01366) and the reduced expression of p14 (p < 0.0001) and p16 (p < 0.0001) proteins were significantly more frequently observed in RC components than in MX components. Reduced expression of p14 protein correlated significantly with hypermethylation of the p14(ARF) gene promoter (p = 0.0176) and over-expression of p53 protein (p = 0.00837). By univariate analysis, reduced expression of p14 and p53 missense mutation were found to reduce the rate of survival significantly (p < 0.05). Multivariate analysis, including clinicopathological factors, revealed that tumour site (p = 0.0251), the presence of an RC component (p = 0.0113), high MIB-1 labelling index (p = 0.0005) and p53 missense mutation (p = 0.0036) were adverse prognostic factors. In MLS/RCLS, reduction of p14 protein expression and p53 mutation were related to poor prognosis. Accordingly, the p14(ARF)/p53 pathway may contribute to the presence of an RC component and malignant progression in this tumour.
在黏液样/圆形细胞脂肪肉瘤（MLS/RCLS）中，据报道圆形细胞（RC）成分的存在与患者预后较差相关。然而，对于该肿瘤中传统黏液样（MX）成分和RC成分之间的分子遗传学差异知之甚少。本研究的目的是调查G1至S期检查点基因分子改变的可能影响，尤其是在RC成分中。我们评估了90例患者中29个RC成分和81个MX成分中p53、MDM2、p14和p16蛋白的免疫组化表达，并使用MIB-1评估增殖活性。还使用一致的石蜡包埋和冷冻材料研究了p53基因的突变、MDM2基因的扩增、纯合缺失、p16（INK4a）/p14（ARF）基因的甲基化状态和突变。将数据与临床病理因素一起分析，以评估它们在MLS/RCLS中的预后意义。免疫组化显示，与MX成分相比，RC成分中p53蛋白的过表达（p = 0.01366）以及p14（p < 0.0001）和p16（p < 0.0001）蛋白的表达降低更为常见。p14蛋白表达降低与p14（ARF）基因启动子的高甲基化（p = 0.0176）和p53蛋白的过表达（p = 0.00837）显著相关。单因素分析发现，p14表达降低和p53错义突变显著降低生存率（p < 0.05）。包括临床病理因素的多因素分析显示，肿瘤部位（p = 0.0251）、RC成分的存在（p = 0.0113）、高MIB-1标记指数（p = 0.0005）和p53错义突变（p = 0.0036）是不良预后因素。在MLS/RCLS中，p14蛋白表达降低和p53突变与预后不良有关。因此，p14（ARF）/p53途径可能促成该肿瘤中RC成分的存在和恶性进展。
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