Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

Charles Li, Elena Bonazzoli, Stefania Bellone, Jungmin Choi, Weilai Dong, Gulden Menderes, Gary Altwerger, Chanhee Han, Aranzazu Manzano, Anna Bianchi, Francesca Pettinella, Paola Manara, Salvatore Lopez, Ghanshyam Yadav, Francesco Riccio, Luca Zammataro, Burak Zeybek, Yang Yang-Hartwich, Natalia Buza, Pei HuiSerena Wong, Antonella Ravaggi, Eliana Bignotti, Chiara Romani, Paola Todeschini, Laura Zanotti, Valentina Zizioli, Franco Odicino, Sergio Pecorelli, Laura Ardighieri, Dan Arin Silasi, Babak Litkouhi, Elena Ratner, Masoud Azodi, Gloria S. Huang, Peter E. Schwartz, Richard P. Lifton, Joseph Schlessinger, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Ovarian cancer remains the most lethal gynecologic malignancy. We analyzed the mutational landscape of 64 primary, 41 metastatic, and 17 recurrent fresh-frozen tumors from 77 patients along with matched normal DNA, by whole-exome sequencing (WES). We also sequenced 13 pairs of synchronous bilateral ovarian cancer (SBOC) to evaluate the evolutionary history. Lastly, to search for therapeutic targets, we evaluated the activity of the Bromodomain and Extra-Terminal motif (BET) inhibitor GS-626510 on primary tumors and xenografts harboring c-MYC amplifications. In line with previous studies, the large majority of germline and somatic mutations were found in BRCA1/2 (21%) and TP53 (86%) genes, respectively. Among mutations in known cancer driver genes, 77% were transmitted from primary tumors to metastatic tumors, and 80% from primary to recurrent tumors, indicating that driver mutations are commonly retained during ovarian cancer evolution. Importantly, the number, mutation spectra, and signatures in matched primary–metastatic tumors were extremely similar, suggesting transcoelomic metastases as an early dissemination process using preexisting metastatic ability rather than an evolution model. Similarly, comparison of SBOC showed extensive sharing of somatic mutations, unequivocally indicating a common ancestry in all cases. Among the 17 patients with matched tumors, four patients gained PIK3CA amplifications and two patients gained c-MYC amplifications in the recurrent tumors, with no loss of amplification or gain of deletions. Primary cell lines and xenografts derived from chemotherapy-resistant tumors demonstrated sensitivity to JQ1 and GS-626510 (P = 0.01), suggesting that oral BET inhibitors represent a class of personalized therapeutics in patients harboring recurrent/chemotherapy-resistant disease.

Original languageEnglish
Pages (from-to)619-624
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number2
DOIs
Publication statusPublished - 2019 Jan 8
Externally publishedYes

Keywords

  • BET inhibitors
  • Bilateral ovarian tumors
  • Ovarian carcinoma
  • Whole-exome sequencing

ASJC Scopus subject areas

  • General

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