Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition
| العنوان: | Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition |
|---|---|
| المؤلفون: | Moses Lee, Serena Wong, Carlton L. Schwab, Emiliano Cocco, Laura Zanotti, Franco Odicino, Pei Hui, Federica Predolini, Charles M. Quick, Peter E. Schwartz, Chiara Romani, Elena Bonazzoli, Antonella Ravaggi, Sergio Pecorelli, Joseph Schlessinger, Stefania Bellone, Titus J. Boggon, Renata A. Tassi, Carla Donzelli, Richard P. Lifton, Amy L. Stiegler, Murim Choi, Roberto Angioli, Salvatore Lopez, Laura Ardighieri, Alessandro D. Santin, Paola Todeschini, Elisabetta Bandiera, Jungmin Choi, Jonathan Black, Mark Bi, Babak Edraki, Masoud Azodi, Fabio Facchetti, Kaya Bilguvar, Natalia Buza, Shrikant Mane, Siming Zhao, Elena Ratner, Durga Thakral, Corrado Terranova, Marcella Falchetti, Dan-Arin Silasi, Eliana Bignotti, Diana P. English, Luca Zammataro, Maysa M. Abu-Khalaf |
| المصدر: | Proceedings of the National Academy of Sciences. 113:12238-12243 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Exome sequencing, 0301 basic medicine, Epithelial-Mesenchymal Transition, Class I Phosphatidylinositol 3-Kinases, Ovarian carcinosarcoma, Uterine carcinosarcoma, Multidisciplinary, Uterine serous carcinoma, Histones, 03 medical and health sciences, 0302 clinical medicine, Carcinosarcoma, Gene cluster, Histone H2A, medicine, Carcinoma, Humans, PTEN, Epithelial–mesenchymal transition, Telomerase, Aged, Aged, 80 and over, Ovarian Neoplasms, biology, PTEN Phosphohydrolase, Biological Sciences, Middle Aged, medicine.disease, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Histone, 030220 oncology & carcinogenesis, Mutation, Uterine Neoplasms, Cancer research, biology.protein, Female, CHD4, Tumor Suppressor Protein p53 |
| الوصف: | Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC. Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial–mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1dafd817797c3f3afa82ce55c3944a54Test https://doi.org/10.1073/pnas.1614120113Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1dafd817797c3f3afa82ce55c3944a54 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
|---|