Department of Pathology, University of California, San Francisco, CA 94115-1656, USA.
Mod Pathol. 2009 Nov;22(11):1477-88. doi: 10.1038/modpathol.2009.119. Epub 2009 Sep 4.
Liposarcoma represents a unique model insofar as some well-differentiated liposarcomas progress to non-lipogenic, so-called 'dedifferentiated,' forms. The well-differentiated and dedifferentiated family of liposarcomas demonstrates amplification of the chromosome subregion 12q13-q15 with resultant amplification of the MDM2 and CDK4 genes. However, the specific genetic changes that distinguish between well-differentiated and dedifferentiated liposarcomas are less well understood. To study the genetic changes in dedifferentiated liposarcomas, paired well-differentiated and dedifferentiated components of 29 tumors were analyzed separately by array-based comparative genomic hybridization. A bacterial artificial chromosome array at approximately 1-Mb resolution was used. The genetic changes were compared with clinical presentation, grade of the dedifferentiated component and overexpression of MDM2 and CDK4. Most tumors (n=21, 72%) were retroperitoneal, with both components present at initial diagnosis (n=25, 86%). Eight tumors (28%) were classified as low-grade dedifferentiation. In four cases (14%), a well-differentiated liposarcoma preceded the presentation of the dedifferentiated tumor by 1-5 years. 12q13-q15 was amplified in all tumors. Using unsupervised hierarchical clustering of copy-number changes, all but two tumors showed close similarities between well-differentiated and dedifferentiated components, and segregated as pairs. Dedifferentiated components had more total amplifications (P=0.008) and a trend for gain at 19q13.2, but no genetic changes were significant in distinguishing between the two components. High-level amplifications of 1p21-32 (n=7, 24%), 1q21-23 (n=9, 31%), 6q23-24 (n=6, 21%) and 12q24 (n=3, 10%) were common, but none significantly correlated with differentiation. Presentation and grade correlated with the frequency of changes at a number of genetic loci (P<0.001), whereas CDK4 immunostaining showed negative correlation with 12q13.13 amplification. The genotypic similarity, at the limit of the array's resolution, between components implies that most genetic changes precede phenotypic 'progression,' early in tumorigenesis. The relationship between genetic changes and presentation or grade may reflect differences in factors that control genomic instability or the background genotype of the tumor.
脂肪肉瘤是一种独特的模型，因为一些分化良好的脂肪肉瘤会发展为非脂形成的、所谓的“去分化”形式。分化良好的和去分化的脂肪肉瘤家族表现为染色体亚区 12q13-q15 的扩增，导致 MDM2 和 CDK4 基因的扩增。然而，区分分化良好的和去分化的脂肪肉瘤的具体遗传变化还不太清楚。为了研究去分化脂肪肉瘤中的遗传变化，我们分别对 29 个肿瘤的分化良好和去分化成分进行了基于阵列的比较基因组杂交分析。使用分辨率约为 1-Mb 的细菌人工染色体阵列。将遗传变化与临床表现、去分化成分的分级以及 MDM2 和 CDK4 的过表达进行比较。大多数肿瘤（n=21，72%）位于腹膜后，初始诊断时两个成分均存在（n=25，86%）。8 个肿瘤（28%）被归类为低度去分化。在 4 例（14%）中，分化良好的脂肪肉瘤在去分化肿瘤出现前 1-5 年出现。所有肿瘤均扩增 12q13-q15。通过无监督层次聚类分析拷贝数变化，除了两个肿瘤外，所有肿瘤的分化良好和去分化成分之间都非常相似，并呈配对分布。去分化成分的总扩增数更多（P=0.008），19q13.2 有获得趋势，但在区分两个成分方面没有任何遗传变化具有统计学意义。1p21-32（n=7，24%）、1q21-23（n=9，31%）、6q23-24（n=6，21%）和 12q24（n=3，10%）的高水平扩增很常见，但均与分化无关。多个遗传位点的改变频率与表现和分级相关（P<0.001），而 CDK4 免疫染色与 12q13.13 扩增呈负相关。在阵列分辨率的极限下，成分之间的基因型相似性表明，大多数遗传变化发生在肿瘤发生的早期，先于表型“进展”。遗传变化与表现或分级之间的关系可能反映了控制基因组不稳定性或肿瘤背景基因型的因素的差异。
