Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas

Abstract

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 amplificationpositive 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 (Z3 MET copies in Z10% and Z4 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 (Z4 MET copies in Z40% 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.

Type-Specific Cell Line Models for Type-Specific Ovarian Cancer Research

“…As we observed in mutation profiles, our bona-fide CCC cell line panel was representative of clear-cell associated copy number changes (Figure 2, Table 3). Most showed modest copy number gains for HNF1B (5/7) and MET (4/7) , including one with high-level amplification (JHOC-5), similar to previous reports for CCC tumors [53], [56], [57]. Although 3/7 CCC lines showed copy number gain of ERBB2 , in all cases the amplicon segment also encompassed the nearby CCC biomarker HNF1B , and none were positive for HER2 protein expression by IHC (not shown).…”

Multifocal endometriotic lesions associated with cancer are clonal and carry a high mutation burden

“…We observed DNA copy number gains in a number of previously documented CCC‐associated genes, including regions of 17q: HNF1B (5/7), PPM1D (5/7), ERBB2 (4/7), STAT3 (4/7); 3q PIK3CA (4/7); 7q: MET (2/7) and 20q: ZNF217 (6/7), including one high‐level gain of PIK3CA observed in case 7. Despite other reports showing common amplification of MET in CCC , we did not observe any such events in our cohort, neither did we observe classic high‐level amplification of ERBB2 , as has been previously reported in breast and mucinous ovarian cancer .…”

“…Previous studies have identified shared patterns of LOH [10,11] as well as single gene abnormalities [13,15] clonally linking endometriosis adjacent to CCC and ENOCa. We extend these observations, demonstrating that some endometriosis lesions have an extensive subset of the mutations present in the associated CCC, and have thus progressed further towards cancer than was previously appreciated.…”

Antitumor Activity and Induction of TP53-Dependent Apoptosis toward Ovarian Clear Cell Adenocarcinoma by the Dual PI3K/mTOR Inhibitor DS-7423

“…However, PIK3CA mutations are more frequent in OCCA (>40%) than in OSA (<10%) [17]. Although mutations of KRAS and PTEN are rare (<10%), the overexpression of several RTKs has been reported in OCCA, including human epidermal growth factor receptor 2 (HER2) with a frequency of approximately 40% and cMET with a frequency of approximately 30% [18]–[21]. Taken together, these observations suggest that the RTK-PI3K/mTOR signaling axis might be broadly activated in OCCA.…”