Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial–mesenchymal transition

Author:

Zhao Siming,Bellone Stefania,Lopez Salvatore,Thakral Durga,Schwab Carlton,English Diana P.,Black Jonathan,Cocco Emiliano,Choi Jungmin,Zammataro Luca,Predolini Federica,Bonazzoli Elena,Bi Mark,Buza Natalia,Hui Pei,Wong Serena,Abu-Khalaf Maysa,Ravaggi Antonella,Bignotti Eliana,Bandiera Elisabetta,Romani Chiara,Todeschini Paola,Tassi Renata,Zanotti Laura,Odicino Franco,Pecorelli Sergio,Donzelli Carla,Ardighieri Laura,Facchetti Fabio,Falchetti Marcella,Silasi Dan-Arin,Ratner Elena,Azodi Masoud,Schwartz Peter E.,Mane Shrikant,Angioli Roberto,Terranova Corrado,Quick Charles Matthew,Edraki Babak,Bilgüvar Kaya,Lee Moses,Choi Murim,Stiegler Amy L.,Boggon Titus J.,Schlessinger Joseph,Lifton Richard P.,Santin Alessandro D.

Abstract

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.

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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