Department of Pathology, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Sevilla, Spain.
Hum Pathol. 2013 May;44(5):852-9. doi: 10.1016/j.humpath.2012.07.027. Epub 2012 Nov 28.
Endometrial carcinosarcomas are aggressive neoplasias composed of high-grade carcinomatous and sarcomatous elements. The pathogenesis and specific genetic alterations underlying these tumors are still not well known. We analyzed alterations in oncogenes involved in the pathogenesis of endometrial carcinomas that might represent predictive markers for specific therapies. Immunohistochemistry for HER2 (tyrosine kinase-type cell surface receptor HER2) and c-KIT (tyrosine-protein kinase Kit) and fluorescence in situ hybridization for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma receptor tyrosine kinase) were carried out for 76 endometrial carcinosarcoma samples on sequential tissue microarray sections. Analysis of 238 mutations across 19 common oncogenes was performed on 34 samples using the Sequenom OncoCarta Panel (Sequenom, Hamburg, Germany). We observed EGFR, HER2, and c-KIT expression in 71%, 1.5%, and 2.7% of tumors, respectively. EGFR amplification was detected in 11 of 76 endometrial carcinosarcomas (14.5%). Four samples showed both amplification and aneuploidy (5.2%). ALK amplification together with chromosome 2 polysomy was found in 1.3% of endometrial carcinosarcomas. In total, 23 mutations in 9 different oncogenes were detected in 15 (44.1%) of 34 endometrial carcinosarcomas. Five endometrial carcinosarcomas (14.7%) had 2 or more mutations. Eleven tumors (32.3%) had mutations affecting the PI3K (phosphoinositide-3-kinase)/AKT (v-akt murine thymoma viral oncogene homolog 1) (6 mutations in PIK3CA (PI3K catalytic alpha polypeptide) and 1 in AKT) and/or RAS/BRAF (serine/threonine-protein kinase B-raf) pathway (3 KRAS [kirsten RAS oncogene homolog], 2 NRAS [neuroblastoma RAS viral oncogene homolog], and 1 BRAF). Mutations in PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) and/or KIT were found in 5 endometrial carcinosarcomas (14.7%). Finally, we found mutations in MET (met proto-oncogene [hepatocyte growth factor receptor]) in 2 tumors (5.9%) and in EGFR in one (2.9%). Our study evidences mutations in oncogenes in endometrial carcinosarcomas that are targets or modulators of response to specific therapies in other human cancers, with PI3K/AKT being the most frequently altered pathway.
子宫内膜癌肉瘤是由高级别癌性和肉瘤性成分组成的侵袭性肿瘤。这些肿瘤的发病机制和特定的遗传改变仍不清楚。我们分析了参与子宫内膜癌发病机制的致癌基因的改变，这些改变可能代表特定治疗的预测标志物。对 76 例子宫内膜癌肉瘤样本进行了连续组织微阵列切片的 HER2（酪氨酸激酶型细胞表面受体 HER2）和 c-KIT（酪氨酸蛋白激酶 Kit）免疫组化和 EGFR（表皮生长因子受体）和 ALK（间变性淋巴瘤受体酪氨酸激酶）荧光原位杂交。使用 Sequenom OncoCarta 面板（Sequenom，汉堡，德国）对 34 个样本进行了 238 个常见致癌基因的 238 个突变分析。我们观察到 71%、1.5%和 2.7%的肿瘤分别表达 EGFR、HER2 和 c-KIT。在 76 例子宫内膜癌肉瘤中有 11 例（14.5%）检测到 EGFR 扩增。4 个样本显示扩增和非整倍体（5.2%）。在 1.3%的子宫内膜癌肉瘤中发现了 ALK 扩增与 2 号染色体三体。总共在 34 例子宫内膜癌肉瘤中的 15 例（44.1%）检测到 9 个不同致癌基因中的 23 个突变。5 例子宫内膜癌肉瘤（14.7%）有 2 个或更多突变。11 例肿瘤（32.3%）有影响 PI3K（磷酸肌醇 3-激酶）/AKT（v-akt 鼠胸腺瘤病毒癌基因同源物 1）（PI3K 催化 α 多肽 6 个突变和 AKT 中的 1 个突变）和/或 RAS/BRAF（丝氨酸/苏氨酸蛋白激酶 B-raf）途径（3 个 KRAS[克氏 RAS 致癌基因同源物]，2 个 NRAS[神经母细胞瘤 RAS 病毒癌基因同源物]和 1 个 BRAF）。在 5 例子宫内膜癌肉瘤（14.7%）中发现 PDGFRA（血小板衍生生长因子受体，α 多肽）和/或 KIT 突变。最后，我们在 2 例肿瘤（5.9%）中发现了 MET（肝细胞生长因子受体原癌基因）突变，在 1 例肿瘤（2.9%）中发现了 EGFR 突变。我们的研究表明，子宫内膜癌肉瘤中存在致癌基因突变，这些基因突变是其他人类癌症中针对特定治疗的靶点或调节剂，其中 PI3K/AKT 是最常改变的途径。
