Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan.
Mod Pathol. 2012 Jan;25(1):122-30. doi: 10.1038/modpathol.2011.143. Epub 2011 Oct 7.
Our previous study demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. This study was conducted to address how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. We histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases, and selected 11 tumors with synchronous endometriosis and 2 tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed (ie, non-atypical endometrioses and the benign CCAFs) were negative for MET gain. However, low-level (≥3 MET copies in ≥10% and ≥4 MET copies in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in ≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components, wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). These results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive the development and progression of the MET amplification-positive ovarian clear-cell adenocarcinoma.
我们之前的研究表明，在卵巢癌中，MET 基因扩增和 MET 的过表达特异性和普遍存在于透明细胞腺癌组织学中。本研究旨在探讨这些改变如何导致这种高度化疗耐药的卵巢癌的发生和发展。我们对 21 例先前描述的 MET 扩增阳性透明细胞腺癌病例进行了组织学回顾，并选择了 11 例同时存在子宫内膜异位症和 2 例伴有邻近透明细胞腺纤维瘤（CCAF）成分的肿瘤。在这个选定的队列中，使用双原位杂交和免疫组织化学分析这些假定的前体病变和相应的浸润性癌成分中 MET 基因的拷贝数改变和 MET 蛋白表达水平。所有分析的非典型前体病变（即非典型子宫内膜异位症和良性 CCAF）均为 MET 增益阴性。然而，在 4 例（40%）非典型子宫内膜异位症和 1 例交界性 CCAF 中检测到 MET 低水平（≥3 MET 拷贝，≥10%的肿瘤细胞；≥4 MET 拷贝，10-40%的肿瘤细胞）增益。此外，在 5 例（50%）非典型子宫内膜异位症中检测到 MET 高水平（≥4 MET 拷贝，≥40%的肿瘤细胞）增益。在纳入的 13 例病例中，有 4 例（31%）在浸润性癌成分中记录到 MET 增益的肿瘤内异质性，其中所有分化较好的癌成分均表现出 MET 低水平增益，所有相应的低分化癌均表现出高水平增益。MET 过表达的总发生率从非典型形式的前体（0%）逐渐增加，通过非典型形式（67%）和相对分化的癌成分（92%），到低分化癌成分（100%）。这些结果表明，导致 MET 过表达的累积 MET 基因拷贝数改变与更高的肿瘤分级相关，并可能驱动 MET 扩增阳性卵巢透明细胞腺癌的发生和发展。
