Abstract 135: Mutational landscape of uterine and ovarian carcinosarcomas reveals new recurrently-mutated histone core genes as drivers of epithelial-mesenchymal transition

Objective: Carcinosarcomas (CS) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. While an increasing body of evidence supports the origin of both CS elements from a common epithelial cell that undergoes sarcomatous dedifferentiation, limited information is currently available about the role of somatic mutations (SNV) and copy number variations (CNV) in these rare tumors. Accordingly, the objective of our study was to evaluate the genetic landscape of uterine and ovarian CSs by whole-exome-sequencing (WES). Methods: We analyzed the mutational landscape of 63 fresh frozen CS biopsies and 5 primary CS cell lines by WES, most of which were matched to normal DNA from the same patients. We also performed multi region WES in separate carcinoma and sarcoma areas to resolve the genetic architecture and evolutionary histories of CS. Finally, in transfection experiments we validated somatic histone 2A and 2B mutations as potential drivers of epithelial-mesenchymal transition (EMT). Results: Our results demonstrated the presence of two major genetic types of uterine CSs [i.e., uterine serous carcinoma-like (USC) profile and endometrioid carcinoma-like profile (EAC)] and provided evidence that both subtypes, as well as ovarian CS, arise from sarcomatous transformation of carcinomas. In addition to recurrent mutations in cancer genes previously identified in USC and EAC such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4/Mi2b and BCOR, we found an excess of mutations in histones H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone cluster containing these genes. We also found frequent deletions comprising TP53 and MBD3, (a member with CHD4/Mi2b of the NuRD-chromatin-modification-complex), and frequent amplification of chromosome segments containing PIK3CA, CCNE1, TERT and c-MYC. Amplifications of the histone cluster and TERT were significantly more frequent in CS than their epithelial counterparts. Stable transgenic expression H2A and H2B in USC cell lines demonstrated that mutant, but not wild type H2A and H2B increased expression of markers of epithelial-mesenchymal transition (EMT), suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages resulting in these two components. Conclusions: Our results provide new insight into the origins and development of uterine and ovarian CS and defined the genetic landscape of this type of malignant tumor. These findings also suggest new therapeutic targets for these highly aggressive neoplasms. Citation Format: Gulden Menderes, Siming Zhao, Carlton L. Schwab, Salvatore Lopez, Jonathan D. Black, Emiliano Cocco, Stefania Bellone, Dan-Arin Silasi, Elena Ratner, Masoud Azodi, Babak Litkouhi, Peter E. Schwartz, Joseph Schlossinger, Richard Lifton, Alessandro Santin. Mutational landscape of uterine and ovarian carcinosarcomas reveals new recurrently-mutated histone core genes as drivers of epithelial-mesenchymal transition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 135.