Department of Basic Pathology, National Defense Medical College, Saitama, Japan.
Mod Pathol. 2011 Aug;24(8):1146-55. doi: 10.1038/modpathol.2011.70. Epub 2011 Apr 8.
The aim of this study was to assess protein overexpression and gene copy number alterations of MET in ovarian clear-cell adenocarcinoma, and to assess its potential as a novel therapeutic target. Ninety cases of clear-cell adenocarcinoma were analyzed for MET protein overexpression and copy number alterations of the MET gene by immunohistochemistry and brightfield double in situ hybridization, respectively. In addition, 101 cases of the non-clear-cell type ovarian carcinomas at advanced stages were also evaluated for comparison. MET overexpression was assigned when complete membrane staining with moderate or strong intensity was observed in at least 10% of the tumor cells examined. Double in situ hybridization was determined as positive when the tumor exhibited high-level polysomy (≥4 copies in ≥40% of tumor cells) or MET gene amplification. MET overexpression was detected in 20 of 90 clear-cell adenocarcinomas (22%) and none of 111 non-clear-cell type ovarian carcinomas. Double in situ hybridization was positive in 21 of 89 informative clear-cell adenocarcinomas (24%) and only 3 non-clear-cell type ovarian carcinomas (3%). In the whole population, true amplification of the MET gene was detected only in the clear-cell adenocarcinoma histology (five cases, 6%). In clear-cell adenocarcinomas, double in situ hybridization positivity was highly correlated with the presence of MET overexpression and a poorly differentiated histology of tumors (P=0.0105 and 0.00038, respectively). For the patients with clear-cell adenocarcinomas, MET overexpression, as well as advanced clinical stage and the poorly differentiated histology of tumors, was identified as an independent unfavorable prognostic factor for overall survival. In conclusion, among ovarian carcinomas, the amplification of the MET proto-oncogene is highly selective and commonly occurs in clear-cell adenocarcinoma. MET could serve as a biomarker for the prognostication of patients with clear-cell adenocarcinoma and tumor progression, and has potential as a novel therapeutic target for this carcinoma.
本研究旨在评估卵巢透明细胞腺癌中 MET 的蛋白过表达和基因拷贝数改变，并评估其作为一种新的治疗靶点的潜力。通过免疫组织化学和明场双色原位杂交分别分析 90 例透明细胞腺癌中 MET 蛋白过表达和 MET 基因拷贝数改变。此外，还评估了 101 例晚期非透明细胞型卵巢癌作为对照。当至少 10%的肿瘤细胞观察到中等或强强度的完整膜染色时，将 MET 过表达定义为阳性。当肿瘤表现出高水平的多倍体（≥40%的肿瘤细胞中≥4 个拷贝）或 MET 基因扩增时，双荧光原位杂交被确定为阳性。90 例透明细胞腺癌中有 20 例（22%）检测到 MET 过表达，而 111 例非透明细胞型卵巢癌中均未检测到。89 例可评估的透明细胞腺癌中有 21 例（24%）双荧光原位杂交阳性，仅 3 例非透明细胞型卵巢癌（3%）阳性。在整个人群中，仅在透明细胞腺癌组织中检测到 MET 基因的真正扩增（5 例，6%）。在透明细胞腺癌中，双荧光原位杂交阳性与 MET 过表达和肿瘤分化不良密切相关（P=0.0105 和 0.00038）。对于透明细胞腺癌患者，MET 过表达以及临床分期较晚和肿瘤分化不良被确定为总生存的独立不良预后因素。总之，在卵巢癌中，MET 原癌基因的扩增是高度选择性的，常见于透明细胞腺癌。MET 可作为透明细胞腺癌患者预后和肿瘤进展的生物标志物，并有可能成为该癌的一种新的治疗靶点。
