Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas
Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas
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DOI：
10.1038/modpathol.2011.143
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发表时间：
2012-01-01
期刊：
影响因子：
7.5
通讯作者：
Matsubara, Osamu
中科院分区：
文献类型：
--
作者：
Yamamoto, Sohei;Tsuda, Hitoshi;Matsubara, Osamu
我们之前的研究表明，在卵巢癌中，MET基因的扩增和MET的过度表达在透明细胞腺癌组织学中特异且常见。这项研究的目的是探讨这些改变如何促进这种高度化疗耐药的卵巢癌的发生和进展。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 例同时患有子宫内膜异位症的肿瘤和 2 例具有邻近透明细胞腺纤维瘤 (CCAF) 成分的肿瘤。使用双原位杂交和免疫组织化学，分析了这些假定的前体病变和该选定队列中相应的浸润性癌成分中 MET 基因的拷贝数变化和 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）的 MET 增益均为阴性。然而，在 10 例非典型子宫内膜异位症中的 4 例（40%）和 2 例边缘性 CCAF 中的 1 例中检测到低水平的 MET 增益（≥ 10% 的肿瘤细胞中≥ 3 MET 拷贝，10-40% 的肿瘤细胞中≥ 4 MET 拷贝）。此外，在 5 个 (50%) 的非典型子宫内膜异位症中检测到高水平的 MET 增益（>= 40% 的肿瘤细胞中 >= 4 个 MET 拷贝）。在13例入组病例中，有4例（31%）在浸润性癌成分中记录了肿瘤内MET增益的异质性，其中所有相对分化的癌成分均显示低水平的MET增益，而所有相应的低分化癌均显示高水平的MET增益。 MET过表达的总体发生率从非典型癌前体(0%)、非典型癌前体(67%)、相对分化癌成分(92%)、低分化癌成分(100%)逐渐升高。这些结果表明，导致 MET 过度表达的累积 MET 基因拷贝数改变与较高的肿瘤分级相关，并可能驱动 MET 扩增阳性卵巢透明细胞腺癌的发生和进展。现代病理学(2012) 25, 122-130; doi:10.1038/modpathol.2011.143； 2011 年 10 月 7 日在线发布
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. Modern Pathology (2012) 25, 122-130; doi:10.1038/modpathol.2011.143; published online 7 October 2011