Tawbi Hussein, Thomas Dafydd, Lucas David R, Biermann J Sybil, Schuetze Scott M, Hart Anita L, Chugh Rashmi, Baker Laurence H
Department of , Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Oncologist. 2008 Apr;13(4):459-66. doi: 10.1634/theoncologist.2007-0166.
Synovial sarcomas (SnSrcs) and malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal tumors of adolescence and young adulthood. Previous work from our laboratory has demonstrated that SnSrcs express epidermal growth factor receptor (EGFR) and human EGFR (HER)-2/neu. The present study extends that work to examine the expression of EGFR in MPNSTs and the characterization of potential targets of the EGFR tyrosine kinase domain.
Tissue microarrays containing 48 cases of SnSrc and 32 cases of MPNST were stained for EGFR, EGFRvIII, and activated EGFR (pY1068-EGFR). Tumor DNA was extracted from fresh and formalin-fixed, paraffin-embedded tissue blocks and sequenced for exons 17-21 of EGFR and exon 2 of K-ras and b-raf.
Immunohistochemistry (IHC) demonstrated that EGFR is expressed in a majority of SnSrcs and MPNSTs (71% and 62.5%, respectively). EGFRvIII immunoreactivity was negative. IHC was weakly immunopositive for activated EGFR (18.7% and 3.1%, respectively). Sequence analysis of the EGFR genomic DNA did not demonstrate mutations in exons 17-21. No K-ras or b-raf mutations were observed in either tumor type.
Expression of EGFR in SnSrcs and MPNSTs with an intact EGFR/mitogen-activated protein kinase pathway has been hypothesized to contribute to the malignant potential of these tumors. Our study reveals the absence of known activating mutations in EGFR, which suggests that trials of small-molecule inhibitors would be of little clinical benefit. A clinical study of treatment with cetuximab is ongoing and may help elucidate whether blockade of EGFR with antibodies is likely to be more active.
滑膜肉瘤（SnSrcs）和恶性外周神经鞘瘤（MPNSTs）是青少年和青年时期罕见的间充质肿瘤。我们实验室之前的研究表明，SnSrcs表达表皮生长因子受体（EGFR）和人EGFR（HER）-2/neu。本研究扩展了该工作，以检测EGFR在MPNSTs中的表达以及EGFR酪氨酸激酶结构域潜在靶点的特征。
对包含48例SnSrc和32例MPNST的组织芯片进行EGFR、EGFRvIII和活化EGFR（pY1068-EGFR）染色。从新鲜的以及福尔马林固定、石蜡包埋的组织块中提取肿瘤DNA，并对EGFR的第17-21外显子以及K-ras和b-raf的第2外显子进行测序。
免疫组织化学（IHC）显示，大多数SnSrcs和MPNSTs中均表达EGFR（分别为71%和62.5%）。EGFRvIII免疫反应性为阴性。IHC对活化EGFR呈弱阳性（分别为18.7%和3.1%）。EGFR基因组DNA的序列分析未显示第17-21外显子存在突变。在这两种肿瘤类型中均未观察到K-ras或b-raf突变。
推测EGFR在具有完整EGFR/丝裂原活化蛋白激酶途径的SnSrcs和MPNSTs中的表达有助于这些肿瘤的恶性潜能。我们的研究揭示EGFR不存在已知的激活突变，这表明小分子抑制剂试验几乎没有临床益处。西妥昔单抗治疗的临床研究正在进行，可能有助于阐明用抗体阻断EGFR是否可能更有效。
